Vinca dimer indole alkaloids

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 ... 

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 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],... 

C46HjgN40 Mr 810.99, cryst., mp. 216°C, [alp +42 (CHCI3) a dimeric indole alkaloid from Catharanthus roseus (see Vinca alkaloids), composed of two parts vindoline and catharanthine with a 10,3 -linkage. V. is a cytostatically active trace alkaloid and is accompanied by demethylated, deformylated, and deacety-lated alkaloids. V. also occurs in other Catharanthus species such as C. ovalis. C. longifolius, C. trichophyl-lus. It is one of the most important monoterpenoid indole alkaloids. 

Vincristine, leurocrisliae a dimeric indole alkaloid closely related to vinblastine, from Vinca rosea (see Vinca alkaloids). It is used mainly for the treatment of acute leukemia in children, and against various other neoplasmic growths. 

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. 

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. 

The periwinkle plant (Vinca rosa), which is indigenous to Florida, has yielded several indole alkaloids. Two with antineoplastic properties are the dimeric indole-dihydroindole derivatives vinblastine (Velban ) and vincristine (Oncovin ). These agents bind to tubulin, arresting mitosis at the metaphase. 

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

Vinblastine, vincaleucoblastine a dimeric indole-indoline alkaloid, m.p. 211-216°C (d.), [a]])-l-42° (CHClj). Structurally, V. is equivalent to a combination of the alkaloids vindoline and catharidine (see Vinca alkaloids). Very low concentrations of V, accompanied by vindoline and catharidine are present in Vinca rosea. V. is one of the most effective naturally occurring antitumor agents, and is used primarily in the treatment of Hodgkin s disease. 

Vinca alkaloids, Catharanthus alkaloids a group of about 60 iridoid indole alkaloids from Vinca (Catharanthus) spp. Structurally, they are tetra- or penta-cyclic indole derivatives with an iridoid component, e g. vindoline, [a]n -18° (CHCI3), m.p. 174-176°C, and vincamine, [ci]d + 41° (pyridine), m.p. 232-233 °C. These are accompanied in the leaves by small quantities (about 0.005%) of two dimeric V.a., i.e. Vinblastine (see) and fincristine (see) (Hg.). Tryptophan and mevalonic acid are biosynthetic precursors... 

Since anti-malignant properties in the Vinca rosea alkaloids are apparently confined solely to certain of the dimeric indole compounds, there being no... 

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]... 

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. 

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