CATHARANTHUS ALKALOIDS
DEEKSHA PAHWA
B.PHARM PUNJAB UNIVERSITY CHANDIGARH
CONTENTS
INTRODUCTION
CATHARANTHU CATHARANTHUS S ALKALOIDS 1. Intr Introd oduc ucti tion on 2. Extractio Extraction n procedure proceduress of Vinca Vinca alkal alkaloids oids 3. Biosynthe Biosynthesis sis of of Cathara Catharanthus nthus alkaloid alkaloidss 4. Cell Cell and and org organ an cultur cultures es Semi-synthetic etic procedures procedures of productio production n of vinblastin vinblastinee 5. Semi-synth and vincristine 6. Mech Mechan anis ism m of act actio ion n 7. Clinical Clinical indica indications tions of of the Vinca Vinca alkalo alkaloids ids 8. Toxici xicitty 9. Effect of weather on the production of alkaloids in C.
roseus 10.Chemical Modifications of the Vinca Vinca alkaloids leading to the synthesis of novel alkaloids 11. Other
novel
cytotoxic
alkaloids
isolated
fro from
Catharanthus roseus. 12. Vinca alkaloids in clinical trials.
TABLE : Vinca Alkaloids: Comparative Pharmacokinetic and Toxicologic Characteristics REFERENCES
INTRODUCTION
The genus Catharanthus (Family- Apocynaceae) is comprised of eight species of mostly perennial herbs. The single species Catharanthus pusillus is native to India. All other species, are native to Madagascar. The chromosome number for all Catharanthus species is 2n = 16. The different species are : • • • • • • • •
Catharanthus coriaceus Markgr. Madagascar. Catharanthus lanceus (Bojer ex A.DC.) Pichon. Madagascar. Madagascar. Catharanthus longifolius (Pichon) Pichon. Madagascar. Catharanthus ovalis Markgr. Madagascar. Catharanthus pusillus (Murray) G.Don. Indian subcontinent. Catharanthus roseus (L.) G.Don. Madagascar Mada gascar.. Catharanthus scitulus (Pichon) Pichon. Madagascar Madagasca r. Catharanthus trichophyllus (Baker) Pichon. Madagascar
Ornamental Ornamental cultivars cultivars of Catharanthus are all derived from species native to roseus and C. trichophyllu trichophylluss has provided the Madagascar Madagascar.. Germplasm Germplasm of C. roseus primary material for development of ornamental cultivars. As an ornamental, Catharanthus, Catharanthus, more commonly known as Madagascar Periwinkle or Vinca is valued for its drought and heat tolerance. In addit additio ion n to its its value value as an herba herbaceo ceous us ornam ornament ental al,, alka alkalo loid id extra extract ctss of Catharanthus roseus have been used in folk medicine as an antidiabetic, diuretic, and antidysenteric, an anti haemorrhagic and for wound healing. In Europe, it was main mainly ly used used as an anti antidi diab abet etic ic,, for for easi easing ng lung lung cong conges esti tion on and and thro throat at inflammation, in south and central Africa; as a poultice to stop bleeding in the US; in India in case of insect stings; against eye inflammation in the Caribbean and as an astringent, diuretic and cough remedy in China. Research on this plant was stimulated by its mention in folklore and investigations starte started d in 1950 for antidi antidiabet abetic ic activi activitie ties. s. Antidi Antidiabet abetic ic activi activity ty could could not be confirmed. However, the test animals became susceptible to bacterial infections on account of transient depression of the bone marrow leading to a net decrease in the number number of circul circulati ating ng leukocy leukocytes tes.. This This led the resear researche chers rs to undert undertake ake extensive extensive examination examination for the possible possible immunosuppr immunosuppressi essive ve principles principles causing causing these these effect effects. s. A number number of dimeri dimericc indole indole alkalo alkaloids ids showin showing g antileu antileukaem kaemic ic activity have subsequently been isolated and two of these, vincaleukoblastine (vinblastine) and leurocristine (vincristine), are now extracted commercially from
C.roseus and used, either alone, or in combination with other forms of therapy for cancer treatment. Catharanthus roseus G. Don., has been variously variously designated designated Vinca rosea L. and Lochnera rosea L. It is a rich source of alkaloids belonging to the category of terpenoid indole alkaloids which are isolated from the three varieties of the plant: (i) ‘roseus’ with violet or rose coloured flowers (ii) ‘albus’ with white flowers and (iii) ‘ocellatus’ with white flowers having red eye. Of these, the red purple variety contains the highest amount of vincristine and vinblastine.
Catharanthus roseus var. roseus
Catharanthus roseus var. ocellatus
Catharanthus roseus var. albus
CATHARANTHUS CATHARANTHUS ALKALOIDS ALKALOID S 1. Introduction The aerial parts of the plant contain co ntain from 0.2 to 1% alkaloids. [1] About 150 roseus.[2] alkaloids have been isolated from Catharanthus roseus. Of particular interest is a group of 20 dimeric alkaloids which contains those with antineoplastic activity, including vincristine and vinblastine. These alkaloids are formed by the coupling of two moieties: an indole moiety and a dihydroindole moiety. moiety. Thus, this led to referring them as “dimer alkaloids” or “bisindole alkaloids. [1] Vinblastine is produced by coupling of two monomer alkaloids catharanthine (indole) and vindoline (dihydroindole), both of which occur free in the plant. Vincristine Vincristine is structurally similar to vinblastine, but has a formyl group rather than a methyl on the indole nitrogen in the vindoline derived portion. Because these alkaloids are only minor constituents of the plant (vincristine is obtained in about 0.0002% yield from the crude drug), large quantities of raw materials are employed in the extraction procedures. Also there is a growing demand for vincristine rather than vinblastine, but the plant produces a much higher proportion of vinblastine. Fortunately, it is now pos possi sibl blee to conve convert rt vinbl vinblas asti tine ne into into vinc vincri rist stin inee eith either er chemi chemical cally ly or via via a [2] microbiological N-demethylation using Streptomyces albogriseolus. Other binary alkaloids which are active are leurosidine (20’-epivinblastine), leurosine (15’, 20’-epoxy vinblastine). [1] Some Some alkal alkaloi oids ds,, for for examp example le,, ajma ajmali lici cine ne,, lochn lochner erin ine, e, serp serpen enti tine ne and and [2] tetrahydroalstonine, also occur in other genera of the family. family.
2. Extraction procedures of Vinca alkaloids Various extraction procedures employed are: a. b. b. c. d.
Superc Supercrit ritica icall fluid fluid extr extract action ion (SF (SFE) E) Soxh Soxhle lett extr extract actio ion n Soli Solidd-li liqu quid id ext extra ract ctio ion n Hot Hot wate waterr extr extract actio ion n
Supercritical fluid extraction Supercritical temperature of a substance is one above which the substance can no longer exist as a liquid, no matter how much pressure is applied. Similarly, supercritical pressure is a pressure above which a substance can no longer exist as a gas, no matter how high the temperature is raised. Under these conditions, the gas and liquid phases both possess the same density and no division exists between between the two phases phases.. This This is the “criti “critical cal state” state”.. In practi practice, ce, conditi conditions ons somewhat above the critical temperature and pressure for a particular substance are usually used and these “supercritical fluids” exhibit properties intermediate bet betwee ween n thos thosee of the the liqui liquid d and gaseou gaseouss phas phases es.. Most Most commo commonly nly used used is o supercriti supercritical cal fluid fluid carbon dioxide (tc = 31 C and pc = 74atm). To render it more polar, a small amount of modifier, e.g. methanol, may be added to the carbon dioxide.[6] Other substances under development for use as supercritical fluids in SFE are: ethane, ethane, propane and nitrous oxide. In case case of vinc vincaa alka alkalo loid ids, s, vind vindol olin inee is extr extract acted ed by SFE. SFE. Accor Accordi ding ng to an optimi optimizat zation ion study study conduct conducted ed for the proces process, s, a remark remarkably ably high content content of vindoline, 58 wt% was extracted from the leaves of Catharanthus of Catharanthus roseus using o SFE under conditions of temperature as 35 C and the pressure being 300 bars. The addition of 3 wt% ethanol as a cosolvent, only slightly improved the extraction yields.[3] Solid-liquid extraction The plant extract from C. roseus is a complex mixture of alkaloids with a wide rang rangee of pola polari riti ties es.. The The trad tradit itio iona nall soli solidd-li liqui quid d extr extract actio ion n proce procedu dure re for for Catharanthus alkaloids from an aqueous acidic medium is based on their general basic basic proper propertie ties. s. The alkalo alkaloids ids form form salts salts in aqueous aqueous acidic acidic media, media, showin showing g improved solubility and enhanced stability at low pH values. In addition, protons in the aqueous acidic media assist in breaking the sample matrix to release the analytes more easily. easily. As a further modification of the above process, water insoluble embonic acid complexes of catharanthine and vindoline were prepared by adding an aqueous alka alkalline ine (pH (pH 10.5 10.5)) solut olutiion of embo emboni nicc acid acid (4,4’ 4,4’-m -met ethy hyle lene ne-b -biis-3s-3hydroxynaphtalenecarboxylic acid) to the aqueous acidic solution (pH 1.5) of the plant extract containing the alkaloids as their soluble hydrochloride salts. The alkaloids were exhaustively precipitated when pH 5 was reached during this proce process. ss. The precipi precipitat tatee mostly mostly consis consisted ted of stable stable embonat embonatee complex complexes es of catharanthine and vindoline, which were useful starting materials for vinblastine synthesis.[4] According to a recent study conducted, SFE method of extraction from dried leaves of C.roseus of C.roseus was optimized to give higher yields of the pharmacologicall pharmacologically y important indole alkaloids. Quantification of the alkaloid concentration was in the
range of 0.18 - 31 microg/ml. The yields obtained for catharanthine, vindoline, vinblastine and vincristine were 2.7, 2.0, 1.3and 1.1 microg/g.[5] Also different methods of extraction were compared for various indole alkaloids and best recoveries for catharanthine (100%) were obtained using SFE at 250 bar and 80oC, using 6.6vol% methanol as modifier for 40 minutes; for vindoline by Soxh Soxhle lett extr extract actio ion n usin using g dichl dichlor orom omet ethan hanee in a refl reflux ux for1 for16 6 hour hours; s; and for for 3’,4’3’,4’-anhy anhydr drovi ovinbla nblasti stine ne by solidsolid-liq liquid uid extrac extractio tion n using using a soluti solution on of 0.5M [5] H2SO4 and methanol (3:1v/v) in an ultrasonic bath for 3hours.
3. Biosynthesis of Catharanthus Catharanthus alkaloids The variou variouss Cathar Catharant anthus hus alkalo alkaloids ids belong belong to the class class of terpeno terpenoid id indole indole alkal alkaloi oids ds,, that that is, is, they they cons consis istt of two two moie moieti ties es deriv derived ed from from two two separ separat atee metabolic pathways- The Mevalonate pathway which gives the non tryptophan moiety; and the tryptophan moiety is obtained from tryptophan. The complex structure of these alkaloids usually contains two nitrogen atoms; one is the indole nitrogen (in the tryptophan- derived moiety) and the second is generally two carbons removed from the Beta- position of the indole ring. ring. The non- tryptophan moiety is derived from mevalonic acid and it is a C10-geraniol (monoterpenoid) cont contri ribu buti tion on in the the case case of thes thesee alka alkalo loid ids. s. This This port portio ion n with with suit suitab able le rearrangements leads to formation of three types of alkaloids(i) Coryanthe- type alkaloids (ii) Iboga- type alkaloids (iii) Aspidosperma- type alkaloids it is believed that the coryanthe- type monoterpenoid moiety is metabolically most primitive. The reactive form of terpene involves an aldehyde group. The loss of one carbon atom during biogenesis, to give C9 unit is largely common. Gerani Geraniol ol by a series series of convers conversion ionss forms forms logani loganin n and then then secolo secologani ganin n (a monoterpenoid monoterpenoid glucoside). glucoside). The molecular molecular characterizat characterization ion of CYP72A1 CYP72A1 from Catharanthus roseus was described nearly a decade ago, but the enzyme function remained unknown. However in a recent study conducted, it was shown that CYP72A1 converts loganin into secologanin.[56] A key intermediate in the biogenesis of the monoterpene indole alkaloids is 3alpha (S)- strictosidine, formed by the enzymatic conden sation of tryptamine and secologanin. The enzyme responsible for this important reaction, strictosidine synthase, has been isolated and characterized from cell cultures of a number of roseus. species including Catharanthus roseus. Strict Strictosi osidin dinee then then leads leads to format formation ion of cathen cathenami amine ne (a coryant coryanthehe- type type of alkaloid); enzyme involved is cathenamine synthase. Cathenamine further gives
rise to ajmalicine (enzyme- ajmalicine synthase) and serpentine. Both ajmalicine and serpentine are also coryanthe- type alkaloids. Cathenamine through a series of reactions also leads to formation of catharanthine (iboga- type) and vindoline (asp (aspid idos ospe perm rmaa- type type). ). Cath Cathar arant anthi hine ne and vind vindol olin inee are are monom monomer eric ic indo indole le alkal alkaloi oids ds and and occur occur free free in the the plan plant. t. 3’,4 3’,4’’-An Anhyd hydro rovi vinbl nblas asti tine ne is a key intermediate from the coupling of catharanthine and vindoline and the enzymes involved are peroxidases. It is further converted to vinblastine.
4. Cell and organ cultures In efforts to improve the production of alkaloids, cell cultures of C.roseus of C.roseus have received considerable attention. Earlier attempts at production in cell cultures failed because a part of the complex pathway was not active, i.e. from tabersonine to vindol vindoline ine.. The enzyme enzyme respons responsibl iblee for the convers conversion ion is tabers tabersoni onine ne 16hydroxylase (T16H), a cytochrome P450-dependent enzyme. However, later it was found that T16H is induced in the suspension culture by light. [51] To date success has been achieved in obtaining total alkaloid yields corresponding to 0.1 – 1.5% (dry weight, cultivated cells). Alkaloids including catharanthine, vindoline and ajmalicine have been identified and isolated from these cell lines; however, the more useful dimeric alkaloids have only been isolated in traces from the cell cultures. [2] It has been observed that leaf organ cultures of C.roseus synthesize a variety of alkaloids. Also dimeric alkaloids have been detected in organ cultures of C.roseus of C.roseus,, suggesting the possibility of an efficient production system for these valuable alkalo alkaloids ids.. The dimers dimers occurre occurred d only in those those cultur cultures es which which also also contain contained ed [9] vindoline and catharanthine. However in a research conducted recently, the final dimerization step of the terpino terpinoid id indole indole pathway pathway,, leadin leading g to the synthe synthesis sis of the dimeri dimericc alkalo alkaloid, id, vinblastine, was demonstrated to be catalyzed by a basic peroxidase and for the firs firstt time time the the clon clonin ing, g, char charac acte teri rizat zatio ion n and and local localiz izat atio ion n of a novel novel basi basicc peroxidase, CrPrx (Catharanthus (Catharanthus roseus peroxidase), from C. roseus was done. The CrPrx nucleotide sequence encodes a translation product of 330 amino acids with a 21 amino acid signal peptide, suggesting that CrPrx is secretory in nature. The molecular mass of this unprocessed and unmodified protein is estimated to be 37.43 kDa. CrPrx was found to belong to a 'three intron' category of gene that encodes a class III basic secretory peroxidase. CrPrx protein and mRNA were found to be present in specific organs and were regulated by different stress treatments.
It is proposed that CrPrx is involved in cell wall synthesis, and also that the gene is induced under methyl jasmonate treatment indicating its potential involvement in the terpenoid indole alkaloid biosynthetic pathway pathwa y. [55] In one of the experiments conducted, a two-liquid-phase bioreactor was designed to extract indole alkaloids from C.roseus ‘hairy root cultures’, using silicon oil. Partition studies between silicon oil and culture medium showed that the affinity of tabersonine and löchnericine for silicon oil is nine times higher than for the aqueous phase. Also, all measured alkaloids' specific yields were higher using silicon oil and elicit elicitati ation, on, sugges suggestin ting g that that the silico silicon n oil, oil, by acting acting as a metabol metabolic ic sink sink for tabersonine and löchnericine, decreased their negative feedback effect on the production of the other useful alkaloids in the aqueous medium and so was efficient in increasing metabolic fluxes of the secondary metabolism pathways. [10] The The trans transfo form rmed ed root root cultu culture re seems seems to be the the most most prom promis isin ing g for for alkal alkaloi oid d production. The genetically transformed roots, obtained by the infection with Agrobacterium rhizogenes, produce higher levels of secondary metabolites than intact plants. Also, whole plants can be regenerated from hairy roots. The content of indole alkaloids in the transformed roots was similar or even higher when compared to the amounts measured in studies of natural roots. The predominant alkal alkaloi oids ds in tran transf sfor orme med d root rootss are are ajma ajmali lici cine, ne, serp serpen enti tine ne,, vind vindol olin inee and and catharanthine, found in higher amounts than in untransformed roots. Transformed hairy roots have been also used for encapsulation in calcium alginate to form artificial seeds.[57] •
Role of the Non-Mevalonate Pathway in Indole Alkaloid Production by Catharanthus roseus Hairy Roots :
The 1-deoxy-D-xylulose-5-phosphate (DXP) pathway (non-mevalonate pathway) leading to terpenoids via isopentenyl diphosphate (IPP) has been shown to occur in most most bact bacter eria ia and and in all all high higher er plan plants ts.. Treat reatme ment nt with with the the anti antibi biot otic ic fosmid fosmidomy omycin, cin, a specif specific ic inhibi inhibitor tor of DXP reduct reductois oisome omeras rase, e, consid considera erably bly inhi inhibi bite ted d the the accum accumul ulat atio ion n of the the alkal alkaloi oids ds ajma ajmali lici cine ne,, tabe tabers rsoni onine, ne, and and lochnericine by Catharanthus roseus hairy root cultures in the exponential growth phase. These results suggest that the DXP pathway is a major provider of carbon for the monoterpenoid pathway leading to the formation of indole alkaloids in C. roseus hairy roots in the exponential phase.[58]
5. Semi-s Semi-synt ynthet hetic ic pr proce ocedur dures es of pr produ oducti ction on of vinbla vinblast stine ine and vincristine
Vindo indoli line ne and and catha cathara rant nthi hine ne are are the the majo majorr mono monome merr alka alkalo loid idss as well well as biosynthetic precursors for the "dimeric" alkaloids, vinblastine and vincristine. Low "dimeric" alkaloid contents in the plant have encouraged intense research for alternative production methods involving cell cultures,[18,19] metabolic engineering,[20] semi-synthesis,[21,22] or even total total chemic chemical al synth synthesi esis. s.[23] Total synthesis has proved difficult due to structural complexity of the molecules and complicated reaction steps involving stereochemical constraints. Various semisynthetic procedures have been developed for these alkaloids on the basis of chemical[21,22] or enzymatic[24] coupling of commercially available catharanthine and vindoline. The presen presentt semi-s semi-syn ynthet thetic ic proces processs is partia partially lly based based on an earlie earlierr method method involving photoactivation of catharanthine, as well as photolytic singlet oxygen production in an aqueous reaction solution.[9] In that method the high energy needed for singlet oxygen production from water, however, results in excessive catharanthine consumption by many side reactions. As an improvement to the above photochemical method, singlet oxygen (1O2) is here produced in situ from hydrogen peroxide and sodium hypochlorite [19]. An allylic hydrogen in the protonated catharanthine moiety is presumably attacked by singlet oxygen to yield a hydroperoxide of catharanthine which then possibly undergoes reduction in the presence of sodium borohydride. Then a final aromatic substitution reaction yields vinblastine through the crucial C18'-C15 bond linking the the top top indo indole le half half of the the cath cathar aran anth thin inee moie moiety ty (C18 (C18') ') and and the the bott bottom om dihydroindole half of the vindoline moiety (C15).
6. Mechanism of action Vinblastine and vincristine are antimitotics. They bind to tubulin and prevent the formation of the microtubules which help in the formation of the mitotic spindle. Thus, these compounds block mitosis and cause an accumulation of cells in the meta metaph phas asee (“me (“meta taph phas asee arre arrest st”) ”)..[11-16] This con contributes to their eir major [1] pharmacological action. The microt microtubul ubulee assemb assembly ly also also plays plays a role role at other other levels levels,, particu particular larly ly in neurotr neurotrans ansmis missio sion n (axon (axon microt microtubu ubules les). ). Hence Hence blockad blockadee of this this activi activity ty is [1] responsible for the neurotoxicity caused as a side e ffect by these alkaloids. They are generally in vitro inhibitors of the biosynthesis of protein and nucleic acid, elevate oxidized glutathione, alter lipid metabolism and membrane lipids, elevat elevatee cyclic cyclic AMP and inhibi inhibitt calciu calcium-c m-calm almodul odulin in regula regulated ted cycli cyclicc AMP [17] phosphodiesterase.
The treatm treatment ent of cell cell popula populatio tion n with with vincri vincristi stine ne or vinblas vinblastin tine, e, leads leads to an accumulation of cells in the M and G2 phase and the effect is lethal in the S phase.[1]
7. Clinical indications of the Vinca alkaloids Vincristine is used more commonly to treat pediatric malignancies, which likely reflects a combination of the higher level of sensitivity of pediatric malignancies to vincristine and to the better tolerance of higher vincristine doses in children. In both children and adults, however, vincristine is an essential component of the chemotherapy regimens used to treat acute lymphocytic leukemia, lymphoid blast cris crisis is of chro chroni nicc myel myeloi oid d leuk leukem emia ia,, and both both Hodgk Hodgkin in and nonnon-Ho Hodgk dgkin in lymphomas. It also plays a role in some multimodality therapies of Wilms tumor, Ewin Ewing g sarc sarcom oma, a, neur neurob obla last stoma oma,, and and rhab rhabdom domy yosar osarcom coma, a, as well well as in the the [34] treatment of multiple myeloma and small-cell lung cancer in adults.
Vincristine
On the other hand, vinblastine has been a mainstay component of chemotherapy regimens for germ cell malignancies and some t ypes of advanced lymphomas. On a historical note, vinblastine has also been used alone or in combination with other agents to treat Kaposi sarcoma and bladder, breast, and some types of brain malignancies.[34] Vincristine has a superior antitumour activity as compared with vinblastine, but the former is more neurotoxic.[2]
Vinblastine
Desa Desace cety tyll vinbl vinblas asti tine ne (vin (vinde desi sine) ne),, init initia iall lly y iden identi tifi fied ed as a meta metabol bolit itee of [25-29] vinblastine, was introduced in the 1970s. Vindesine is available only for investigational purposes in the United States, but is registered elsewhere. The agent was principally evaluated in combination with other agents, particularly cisplatin and/or mitomycin C, in treating non-small-cell lung cancer, but it has also demonstrated consistently favorable results in several hematologic and solid malignancies.[28,29]
V inde sine The newer, orally active,[2] vinblastine derivative semi-synthesized by Potier et al. Vinorelbine (5’-norhydro Vinblastine), has broader anticancer activity and lower neurotoxic side-effects than the other Catharanthus other Catharanthus alkaloids.[8] It is structurally modi modifi fied ed on its its catha cathara rant nthi hine ne nucl nucleu eus, s, resu result ltin ing g in subs substa tant ntia iall lly y great greater er lipophilicity as compared to the other Vinca alkaloids. The potent antitumor effect of Vinorelbine with minor neurotoxicity was explained by Vinorelbine having stronger activity on mitotic microtubules than axonal microtubules.[53] It is effective in combination with chemotherapeutic agents such as anthracycline, fluorouracil and Taxol. It is approved in the United States for treating non-smallcell lung cancer as either a single agent or in combination with cisplatin, and has been registered to treat patients with advanced breast cancer elsewhere. [30-33] Vinorel inorelbin binee has also also demonst demonstrat rated ed antica anticancer ncer activi activity ty in advanced advanced ovaria ovarian n carci carcinom nomaa and and lymp lymphom homa; a; howe however ver,, a uniq unique ue role role in the the ther therapy apy of thes thesee malignancies has not been defined.
Vinorelbine Tartrate
8. Toxicity Although the Vinca alkaloids are quite similar from a structural standpoint, their toxico toxicolog logic ic profil profiles es differ differ signif significa icantl ntly y. All of the Vinca inca alkalo alkaloids ids induce induce a characteristic peripheral neurotoxicity, but VCR is most potent in this regard. The neuroto neurotoxic xicity ity is princip principall ally y charact characteri erized zed by a periph periphera eral, l, symmet symmetric ric mixed mixed [32,35,36,37-41] sensory-motor, and autonomic polyneuropathy. The primary pathologic effect effect is axonal degeneration degeneration and decreased decreased axonal transport, transport, most likely caused by a drug-induced perturbation of microtubule function. Toxic manifestati manifestations ons include constipatio constipation, n, abdominal abdominal cramps, cramps, paralytic paralytic ileus, urinary retention, orthostatic hypotension, and hypertension. severe neurotoxicity is observed less frequently with VBL, VDS, and VRL, as compared to VCR.[42,43] VRL has a lower affinity for axonal microtubules than either VCR or VBL, which seems to be confirmed by clinical observations.[30-32,43,44] VCR treatment in patients with hepatic dysfunction or obstructive liver disease is associated with an increased risk of developing neuropathy because of impaired drug metabolism and delayed biliary excretion. Neutropenia is the principal doselimiting toxicity of VBL, VDS, and VRL. Thrombocytopenia and anemia are usually less common and less severe.
Gastrointestinal toxicities, aside from those caused by autonomic dysfunction, may be caused by all the Vinca alkaloids. [26,28,37,38,41,46] Mucositis occurs more frequently with VBL than VRL or VDS, and is least common with VCR. Nausea, vomiting, and diarrhea may also occur to a lesser extent. Pancreatitis has also been reported with VRL. [47] The Vinca alkaloids are potent vesicants and may cause significant tissue damage if extravasati extravasation on occurs. occurs. If extravasation extravasation occurs or is suspected, treatment treatment should should be discontinued immediately and aspiration of any residual drug remaining in the tissues should be attempted. [48] The application of local heat and injection of hyaluronidase, 150 mg subcutaneously, in a circumferential manner around the needle site are thought to minimize both discomfort and latent cellulitis, perhaps by facilitating drug dispersion. Because of their remarkable vesicant properties, the Vinca alkaloids should not be administered intramuscularly, subcutaneously, intravesically, or intraperitoneally. Direct intrathecal injection of VCR and other Vinca alkaloids, which has occurred as inad inadver verte tent nt clin clinic ical al mish mishap aps, s, indu induces ces a seve severe re myel myeloe oence ncepha phalo lopa path thy y characterized by ascending motor and sensory neuropathies, encephalopathy, and rapid death.[26,28,49,50] Mild and reversible alopecia occurs in approximately 10% and 20% of patients treated with VRL and VCR, respectively. respectively. The only known known effec effectiv tivee interv interventi ention on for Vinca inca alkaloi alkaloid d neurot neurotoxi oxicit city y is disc discon onti tinu nuin ing g trea treatm tmen entt or redu reduct ctio ion n of the the dose dose or freq freque uenc ncy y of drug drug administration. Although a number of antidotes, including thiamine, vitamin B12, folini folinicc acid, acid, pyrido pyridoxine xine,, and neuroact neuroactive ive agents agents (eg, (eg, sedati sedatives ves,, tranqui tranquiliz lizers ers,, anticonvulsants), have been used, these treatments have not been clearly shown to be effective.[26,28] Folinic acid protects mice against otherwise lethal doses of the Vinca alkaloids, and there are anecdotal reports of its successful use following VCR VCR overd overdos osage age in man; man; howe however ver,, pros prospe pect ctiv ivee stud studie iess have have never never been been performed.
9. Effect of weather on the production of alkaloids in
C. roseus
In a study one set of plants were grown in rainy season from March-April to SeptOct. Another set was grown in winter season from Sept-Oct to March-Apr. March-Apr. [62]
Vincristine was totally absent from root material. It is also reproted that bisindole alkaloids and vindoline accumulate only in green tissue and are not found in root or cell suspension cultures. Also full sunshine is reported to give a higher sontent of alkaloids than shade. Table-1 Amount of different alkaloid (mg/gm) under difference season in leaf and root material of two varieties of c-roseus Type of Variation Tissue in Season
Rainy Leaf
Winter Rainy
Root
Winter
Variety
Ajmaline
Vincristine Vincristine
Ajmalicine
roseus
1 .0 9
1.39
0 .4
alba
N
3.83
N
roseus
3 .3 8
8.75
0.91
alba
N
N
N
roseus
4 .5 2
N
2.1
alba
N
N
N
roseus
3 .0
N
N
alba
0.8 5
N
N
Table -2 Season
Variety
roseus
Total Alkaloid Leaves (mg/kg) a 45
Roots (mg/kg) a 24
alba roseus
40 48
28 26
alba
39 3 .5
20 2 .8
Rainy
Winter LSD at 5% a = on dry weight basis
Total alkaloid alkaloid content was highest highest in ‘roseus’ ‘roseus’ variety variety during winter. winter. Highest Highest amount of root alkaloid was noted in ‘alba’ variety when grown in rainy season and in ‘roseus’ in winter season. Minimum alkaloid content was noted in ‘alba’ variety during the winter months. Present study showed that seasons have impact on the biomass and alkaloid production, both qualitatively and quantitatively on genotypes of C. of C. roseus and variety ‘roseus’ was found to be superior to variety ‘alba’.
10. Chemical Modifications of the Vinca alkaloids leading to the synthesis of novel alkaloids Severa Severall hundre hundred d derivat derivative ivess have been synthe synthesiz sized ed and evaluat evaluated ed for their their pharmacological activities, the majority being modified in the vindoline moiety, bearing several reactive centers. These efforts led to the identification of the amido derivative vindesine, registered in Europe in 1980 and now available in seve severa rall coun countr trie ies. s. Then Then novel novel chemi chemist stry ry perm permit itte ted d the the semis semisyn ynth thes esis is of derivatives derivatives modified modified in the velbenamine "upper" part of the molecule, creating creating a new potential in the Vinca alkaloids medicinal chemistry: as a result, vinorelbine, obtain obtained ed by C' ring ring contrac contractio tion n of anhydr anhydrovi ovinbla nblasti stine, ne, and is now markete marketed d worl worldw dwid ide. e. Sever Several al stra strate tegi gies es aimed aimed at the the tota totall synt synthes hesis is of vinbl vinblas asti tine ne derivatives have been investigated, giving the opportunity to design rationally certain compounds. Modifications in the D' ring appeared to induce dramatic changes changes in the tubuli tubulin n intera interacti ctions ons.. These These observ observati ations ons have been confirm confirmed ed recent recently ly by the identi identific ficati ation on of unpreced unprecedent ented ed pharmac pharmacolo ologic gical al proper propertie tiess [52] exerted by the novel fluorinated Vinca alkaloid, vinflunine. The two second-generation Vinca alkaloids, vinorelbine and vinflunine, affect microtubule dynamics very differently from vinblastine, a first generation Vinca alkalo alkaloid. id. For example example,, vinblas vinblastin tinee strongl strongly y suppre suppress sses es the rate rate and extent extent of microtubule shortening in vitro, whereas vinorelbine and vinflunine suppress the rate and extent of microtubule growing events. There was doubt whether these differences result in differences in mitotic spindle organization that might be responsible for the superior antitumor activities of the two second-generation Vinca alkaloids. However,Despite differences in their actions on individual dynamic instability parameters, morphologically detectable differences in spindle effects among the
three drugs were minimal, indicating that overall suppression of dynamics may be more important in blocking mitosis than specific effects on growth or shortening. the peak intracellul intracellular ar drug concentratio concentration n at the mitotic mitotic IC(50) value was highest for vinflunine (4.2 +/- 0.2 microM), intermediate for vinorelbine (1.3 +/- 0.1 microM), and more than 10-fold lower for vinblastine (130 +/- 7 nM), suggesting that intracellular binding reservoir(s) may be partially responsible for vinflunine's high efficacy and minimal side effects. [54]
11. Othe Otherr novel cytotoxic cytotoxic alkaloids alkaloids isolated isolated from
Catharanthus
roseus
(i) According According to a recent recent study study,, BM6, a new semi-synt semi-synthetic hetic vinca vinca alkaloid, alkaloid, exhibits its potent in vivo anti-tumor activities via its high binding affinity for tubulin and improved pharmacokinetic profiles. The aim of this study was to evaluate the anti-tumor activities and to establish the mechanism mechanism of the action action of 3-decarboxyl 3-decarboxyl-acety -acetyloxylm loxylmethyl ethyl-anhyd -anhydrovinb rovinblasti lastine ne (BM6). BM6 BM6 was was char charac acte teri rize zed d by its its supe superi rior or in vivo vivo activ activit ity y to vino vinore relb lbin inee in preclinical tumor models, though BM6 exerted in vitro cytotoxic activity against a wide spectrum of tumor cell lines with IC(50) values generally 10-fold higher than the classic Vinca alkaloids. Of note, BM6 displayed more potent cytotoxic activity against multidrug-resistant sublines.
BM6 also induced significant cell cycle arrested in mitosis and cytoskeleton disruption via interacting with the Vinca binding site on tubulin. Encouragingly, the the feat featur ures es in term term of its its high higher er tubu tubuli lin n bind bindin ing g affi affini niti ties es and and bett better er [59] pharmacokinetic profiles highlight BM6 distinct from other Vinca alkaloids. (ii) Two New bisindole bisindole alkaloids, Vingramine Vingramine 1 and Methylvingramine 2, were isolated from the Seeds of Catharanthus of Catharanthus roseus. roseus. Their structures were determined by one- and two-dimensional NMR experiments. They possess a new bisindole skeleton involving an indole alkaloid part B with loss of 5',6'-ethylene, a C7'-C16'
linkage, a 14'-O-19'-tetrahydrofuran, and a N-4'-isobutyramide group. The 12methyl vincorine part A and part B are connected conne cted via an 11,10'-biphenyl linkage. Thes Thesee alkal alkaloi oids ds disp display lay,, in vitr vitro, o, cyto cytoto toxi xicc activ activit ity y agai agains nstt nasop nasophar haryn ynx x [61] carcinoma KB cells.
(iii) (iii) 16-Epi-Z-is 16-Epi-Z-isosits ositsiriki irikine, ne, a monomeri monomericc indole indole alkaloid alkaloid with with antineoplas antineoplastic tic activity from Catharanthus roseus. The compound displayed antineoplastic activity in the KB test system in vitro and the P-388 test system in vivo. [60]
12. Vinca alkaloids in clinical trials Vinflunine : Vinflunine is a new Vinca alkaloid uniquely fluorinated, by the use of superacid chemistry, in a little exploited region of the catharanthine moiety. In vitro investigations have confirmed the mitotic-arresting and tubulin-interacting properties of vinflunine shared by other Vinca other Vinca alkaloids. However, differences in terms of the inhibitory effects of vinflunine on microtubules dynamics and its tubulin binding affinities have been identified which appear to distinguish it from the other Vinca other Vinca alkaloids. Studies investigating the in vitro cytotoxicity of vinflunine in combination therapy have revealed a high level of synergy when vinflunine was combined with either cisplatin, cisplatin, mitomycin mitomycin C, doxorubicin doxorubicin or 5-fluoroura 5-fluorouracil. cil. Furthermore Furthermore,, although although
vinflu vinflunine nine appear appearss to partic participa ipate te in P-gly P-glycopr coprotei otein-m n-medi ediate ated d drug drug resist resistance ance mechanisms, it has proved only a weak substrate for this protein and a far less potent potent inducer inducer of resist resistance ance than than vinore vinorelbi lbine. ne. Vinflun influnine ine was identi identifie fied d in preclinical studies as having marked antitumour activity in vivo against a large panel of experimental tumour models, with tumour regressions being recorded in human renal and small cell lung cancer tumour xenografts. Overall its level of activity was superior to that of vinorelbine in many of the experimental models used. Interestingly, an in vivo study using a well vascularised adenocarcinoma of the colon has suggested that vinflunine mediates its antitumour activity at least in part via an antivascular mechanism, even at sub-cytotoxic doses. Therefore, these data data provid providee a favour favourable able precli preclinic nical al profil profilee for vinflu vinflunin nine, e, suppor supportin ting g its promising candidacy for clinical development. Phase I and Phase II evaluations of vinflunine have been completed in Europe and phase III clinical trials are now ongoing. [62-63]
vinflunine Table-3 Vinca inca Alka Alkalo loid ids: s: Characteristics
Comp Compar arat ativ ivee
Vincristine Formula
C46H56 N N4O10
Phar Pharma maco coki kine neti ticc
Vinblastine
Vindesine
C46H58 N N4O9
C43H55 N N5O7
and
Toxic oxicol olog ogic ic
Vinorelbine C45H54 N N4O8
Standard adult dose range (mg/m2/wk)
1–2
6–8
3–4
15–30
Route
i.v.
i.v.
i.v.
i.v., oral
Bioavailability
n.a.
n.a.
n.a.
79-91%
Protein Binding
~75%
Pharmacokinetic Triphasic behavior Plasma half-lives α (min) <5 β (min) 50–155 γ (h) 23–85 Clearance (L/h/kg)
0.16
~75%
65-75%
43% (oral)
Triphasic
Triphasic
Triphasic
<5 53–99 20–64
<5 55–99 20–24
<5 49–168 18–49
0.74
0 .2 5
0.4–1.29
Primary route
Hepatic Hepatic Hepatic Hepatic metabolism and metabolism and metabolism and metabolism and biliary biliary biliary biliary elimination elimination elimination elimination Principal toxicity Neurotoxicity Neutropenia Neutropenia Neutropenia Othe Otherr toxic toxicit itie iess
Cons Consti tipa pati tion on,, SIADH
Alopecia, neurotoxicity, mucositis
Alopecia, neurotoxicity
Neurotoxicity, vomiting, constipation, mucositis SIADH = syndrome of inappropriate secretion of antidiuretic hormone.
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60. Mukhopadhyay Mukhopadhyay,, S., El-Sayed, El-Sayed, A., Handy, Handy, G.A., Cordell, Cordell, G.A., Catharanthus Catharanthus alkaloids alkaloids XXXVII. XXXVII. 16-Epi-Z-is 16-Epi-Z-isosits ositsiriki irikine, ne, a monomeric monomeric indole alkaloid with stricta. Journal of antineoplastic activity from Catharanthus roseus and Rhazya stricta. Natural Products, 46(3), 1983 May-Jun : 409-13. 61. Gupta Gupta K, Influe Influence nce of season seasonss on biomas biomasss and alkalo alkaloid id produc productiv tivity ity in Catharanthus roseus, roseus, Journal of Medicinal and Aromatic Plant Sciences, Sciences , 24(3) , 2002 : 664-68. 62. A . Kruczynski, Bridget T. Hill, Vinflunine, Vinflunine, the latest Vinca alkaloid in clinical development A review of its preclinical anticancer properties . Critical Reviews in Oncology/Hematology , 40 , Issue 2 : 159 – 173. 63. A . Kruczynski , M . Poli , R ., Dossi , E ., Chazottes , G ., Berrichon , C ., Ricome , R ., Giavazzi , B ., Hill , G ., Taraboletti, Anti-angiogenic, vasculardisrupting and anti-metastatic activities of vinflunine, the latest vinca alkaloid in clinical development . European Journal of Cancer , Cancer , 42 , Issue 16 : 2821 – 2832.
TABLES : Table-1. and Table-2. : Gupta K, Influence of seasons on biomass and alkaloid roseus, Journal of Medicinal and Aromatic Plant productivity in Catharanthus roseus, Sciences, Sciences, 24(3), 2002 : 664-68. Table-3 : Edited by Kufe, Pollock, Wiechselbaum, Bast, Gansler, Holland, Frei, ‘Cancer Medicine’ , 2003, Hamilton•London, UK: BC Decker Inc, Section 12 (53).
