Dimeric vinca alkaloids

Several of the naturally occurring indoles also have clinical importance. The dimeric vinca alkaloid vincristine and closely related compounds were among the first of the anti-mitotic class of chemotherapeutic agents for cancer[14]. The mitomycins[15] and derivatives of ellipticine[16] are other examples of compounds having anti-tumour activity. Reserpine, while not now a major drug, was one of the first compounds to show beneficial effects in treatment of mental disorders[17]... 

Two dimeric Vinca alkaloids, vinorelbine and anhydrovinblastine, have also been investigated using the CHCl3-HF-SbF5 system.550-552 In both cases, the corresponding products difluorinated in the ethyl side chain (140) were isolated in modest yields [Eq. (5.206)]. The mechanistic pathway suggested that the transformation includes steps already depicted in Schemes 5.57 and 5.58. 

He suggests that if this is a general phenomenon of the dimeric Vinca alkaloids, then possibly comparison of the mass spectra of the compounds as the free base and as the sulfate salt may aid in interpretation of the mass spectral data. 

Vindoline and catharanthine are the last monomeric precursors of the dimeric anticancer alkaloids of C. roseus, and they are also the two major alkaloids accumulated in the leaves of the plant [106, 107], The study of the dimerization biosynthetic step stems in early work on the chemical synthesis of the dimeric alkaloids and it has involved much discussion. Moreover, the chemical dimerization reaction has industrial application in the synthesis of vinorelbine and vinflunine. Due to its potential regulatory importance for the production of the dimeric Vinca alkaloids in the plant, and to the much that is known about the chemical and biosynthetic reactions, the dimerization step will be presented in particular detail here. 

The modified Polonovski reaction first used in [19] and later called the Potier-Polonovski reaction, resulted in the formation of an iminium dimer which, after reduction with NaBELt, yielded a-3 ,4 -anhydrovinblastine, Fig. (2). Thus, this was the first dimeric Vinca alkaloid with the natural configuration to be synthesized. This method allowed, subsequently, the development of approaches to the synthesis of other natural dimerics like vinblastine, vincristine, leurosidine and leurosine [110-114], and more recently, to the semisynthetic vinorelbine and vinflunine [16, 22]. 

Because of the resemblance of voacangine to the iboga portion of the dimeric Vinca alkaloids, perivinol has been coupled to vindoline in refluxing methanolic hydrogen chloride. A dimer, perivindoline (II) (sulfate, mp > 300°) was obtained (28) but was found to be inactive against P-1534 leukemia, which is known to be very sensitive to the oncolytic... 

Extensive biotransformation studies have been conducted with the As-pidosperma alkaloid vindoline, but much less work has been done with monomeric Iboga and dimeric alkaloids from this plant. The long-standing interest in this group of compounds stems from the clinical importance of the dimeric alkaloids vincristine and vinblastine, both of which have been used for more than 2 decades in the treatment of cancer. Few mammalian metabolites of dimeric Catharanthus alkaloids have been characterized. Thus the potential role of alkaloid metabolism in mechanism of action or dose-limiting toxicities remains unknown. The fact that little information existed about the metabolic fate of representative Aspidosperma and Iboga alkaloids and Vinca dimers prompted detailed microbial, mammalian enzymatic, and chemical studies with such compounds as vindoline, cleavamine, catharanthine, and their derivatives. Patterns of metabolism observed with the monomeric alkaloids would be expected to occur with the dimeric compounds. 

Because of the previous inaccurate botanical determination of the Madagascan periwinkle, the alkaloids of this plant were formerly considered as Vinca alkaloids, an erroneous subclassification for alkaloids isolated from a plant belonging to the genus Catharanthus. It also should be noted that the alkaloids of C. roseus containing two different (most commonly indole and dihydroindole) alkaloid building blocks were, and sometimes still are, referred to as dimeric indole alkaloids. It is more accurate to use the term binary or bisindole alkaloids, since chemically these alkaloids are not dimers of two equal subunits, but rather comprised of two (bis) different alkaloid building blocks. 

Vinblastine (4) and vincristine (5) are closely related indole-dihydroindole dimers (bisindole alkaloids), isolated from Catharanthus roseus (L.) G. Don (formerly known as Vinca rosea L.), the Madagascar periwinkle. Both of these anticancer agents, known as vinca alkaloids in the medical literature, are specific binders of tubulin, leading to tubulin depolymerization and cell cycle arrest in the metaphase stage. 

Vinca dimer indole alkaloids (e.g. vinbiastine) act as spindle poisons. They bind tubulin, inhibiting polymerisation into microtubules, the major elements of the cytoskeleton [100]. Vinblastine itself and its analogue vinoreibine (Navelbine ) [101] are marketed for cancer therapies (Fig. 36). Vinflunine (Javlor ) is a member of second-generation Vinca dimer alkaloids. This 4 -difluoro analogue is more active than vinoreibine in several cancers (Fig. 36). It is now in phase III clinical... 

Vinca dimer indole alkaloids (e.g., vinblastine) act as spindle poison. They bind tubulin, inhibiting polymerization into microtubules, major elements of the cytoske-Vinblastine itself and its analogue vinorelbine (Navelbine ) are marketed for cancer therapies (Figure 4.48). Because of the obvious difficulty in synthesizing such highly complex structures, there were no reports on the preparation of fluorinated derivatives until the remarkable work of Jacquesy s group on the synthesis in super-acidic media. 5 ... 

The best known drugs acting as antimitotics are the vinca alkaloids, vincristine (7.90) and vinblastine (7.91). They are very complex indole derivatives that nevertheless have been synthesized. Both are quite effective in various leukemias and in Hodgkin s lymphoma, but show considerable neurotoxicity. Vinblastine and vincristine bind specifically to the microtubular protein tubulin in dimeric form, precipitating depolymerization of the microtubules and functionally acting as a mitotic poison. Vinorelbine (7.92) is a semisynthetic vinca alkaloid functionally identical to vinblastine. 

Vinblastine (4 in Chart 1) and its congeners are dimeric indole alkaloids derived from Catharanthus (Vinca) roseus. Nowadays, the vinca alkaloids constitute an important class of widely and successfully used anticancer agents that inhibit tubulin polymerization [8],... 

Figure 10 The stability of a freeze-dried monoclonal antibody/vinca alkaloid conjugate formulation. Desacetylvinblastine hydrazide is linked to the KSl/4 monoclonal antibody via aldehyde residues of the oxidized carbohydrate groups on the antibody. The formulation is conjugate/glycine/mannitol in a I I I weight ratio. Storage temperatures are 25°C and 40°C for samples with moisture contents of 1.4%, 3.0%, and 4.7%. ( ) Dimer formation. (A) Free vinca generation (hydrolysis). ( ) Vinca degradation. (—) Best fit to the WLF equation. (Reproduced with permission from [54].)...

Vindoline belongs to the vinca alkaloids, an important class of indole alkaloids whose dimers (such as vincadifformine) are anti-cancer compounds. The most difficult functionality in this compound is the tertiary a-hydroxyester and Langlois37 proposed to make this by hydroxylation of the related keto-ester 238. 

Such compounds often exhibit chemical and spectral behaviour which is specifically characteristic of the dimeric structure. Also of paramount interest are the specific pharmacological properties of certain of these alkaloids, such as the muscle relaxation action of the curare alkaloids and the anti-leukemia activity of the Vinca alkaloids leurocristine and vinblastine. Such aspects will be discussed in the last two sections of the review. 

The antimitotic mechanism of taxol differs from the antimicrotubule agents such as colchicine and the vinca alkaloids discussed earlier. Rather than causing disassembly of the microtubules, taxol actually enhances tubulin polymerization. This upsets the normal dynamic equilibrium between soluble tubules, which are dimers, and the microtubule polymers. The stabilization of the latter inhibits mitosis in the latter part of Phase G2 and M. Although sharing much of the toxicology of many of the anticancer drugs, taxol promises to be an important addition to the cancer armamentarium. 

The so-called Vinca alkaloids are dimeric terpenoid indole alkaloids well known by their antimitotic activity, which has made them extremely... 

The vinflunine case demonstrated that the Vinca alkaloids remain a drug family where it is still possible to identify new members with unprecedented and promising pharmacological properties. When the ongoing research on the mechanisms of action of Vinca alkaloids unravels the precise relation structure/function of the dimeric molecules, it should be possible to rationally design a new generation of Vinca alkaloids with new therapeutic properties. 

In face of the structural similarities unraveled during the 1960s of vindoline and catharanthine with the dimeric alkaloids, and due to their great abundance in the plant, these two compounds were immediately considered the most likely monomeric precursors of the Vinca alkaloids, although the cleavamine moiety of vinblastine presented some differences from catharanthine, namely a fragmentation of the C5-C18 bond, Fig. (2). 

Vinca alkaloids. Up to this date no perivinol type of dimeric alkaloid has been recognized in F. rosea although vindoline and perivine are major alkaloids of this plant. 

COOCH3 3 C21H24N2O2, Mr 336.43, crystalline, mp. 126-I28°C (CHCI3), 61 - 63 °C (racemate), [aJu +29.8°. C. is a major alkaloid of Catharanthus species. It is the biosynthetic precursor of dimeric Catharanthus (Vinca) alkaloids. C. exhibits moderate blood sugar lowering and diuretic activities. 

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