Binary indole alkaloids

Researchers from Eli Lilly pharmaceuticals, (a company founded in 1876 by Colonel Eli Lilly veteran of the US Civil War), undertook further intensive phytochemical studies and characterized 60 alkaloids, of which a group of 20 binary indole alkaloids—including vincristine and vinblastine. Vinblastine sulphate (Velbe ) inhibits the polymerization of tubulin and is used to treat generalized Hodgkin s disease and chorionepithelioma, whereas vincristine sulphate (Oncovin ) is used to treat leukemia in children. 

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. 

As mentioned in Section 1, molecules as complex as the indole-indoline binary alkaloids warrant an investigation of their critical stereochemistry, including the binary character, with respect to function. The activity profile of the epi C-16, C-14, C-20 -diastereomer of 20 -deoxy VBL is presented in Fig. 5a. The compound inhibits population growth only at micromolar potency, and it lacks detectable antimicrotubule activity. This profile is also typical of the diastereomers of VBL (vincovaline), and of the C-20 congeners examined to date, epideoxy VBL (2), and deoxydesethyl VBL (3). 

The structure-function relationship of the indole-indoline binary alkaloids was relegated to obscurity until the recent achievement of methodologies for their complete syntheses (see Chapter 2, this volume). Our work with C-20 congeners of VBL has established that the complex interactions between this molecule and tubulin or microtubules can be modified by structural alteration. The various, concentration-dependent reactions of VBL with the microtubule system in vitro are sensitive to subtle modifications at a single molecular locus. In addition, these reactions are distinctive on a mechanistic level as seen from the unique activity profiles of most of our C-20 alkyl congeners. At first light, we can look toward the future with secured optimism. 

A recent communication by Kumar and co-workers reported the isolation of a new binary tetrahydrocarbazole-indole alkaloid, methyl 2-methyl-4-(iV-2")8-methyl-l",2",3",4"-tetrahydrocarbazol-l"a-ylindol-3 -yl butanoate (77), C27H30N2O2 from the root timber of Murraya gleniei (67). It exhibited spectral data characteristic of an indole with an ester function. The mass spectral fragments having m/z 231 and 184 indicated that it was a binary alkaloid consisting of C14H17N02 and Q3H14N units. The structure and stereochemistry of 77 were established by the application of 1H, 13C, DEPT,... 

The binary indole-indoline alkaloids vinblastine (VLB, 1) and vincristine (VCR, 2) (Fig. 1) have triggered considerable chemical investigation as a result of their extensive clinical use as antineoplastic agents (2-4), coupled with an arduous isolation from plant material, and because of... 

One of the major difficulties in the synthesis of these binary indole-indoline alkaloids is the necessity of generating the natural PARF (priority antireflective) (12) relative stereochemistry between C-14 and C-16, as well as the requirement for controlling the absolute stereochemistry at C-16, which must be (5). Other epimers at these positions lack the high cytotoxicity, with mitotic arrest at metaphase, that is the basis of the anticancer activity of these compounds (13,14). 

That only the wrong C-16 diastereomer seemed to be produced in this reaction was then demonstrated by the Kutney group, who prepared a series of binary indole-indoline alkaloids using the chloroindolenine approach. The apparent simplicity of this coupling reaction and the rapidity in assembling such binary alkaloids prompted an extensive study of reaction conditions (28), with the desire to find a procedure suitable for generation of the C-16 (S) isomer, required for anticancer activity. Despite the intensive effort involved in this in-depth study, no success could be realized, and it was therefore widely accepted that .. . it is very unlikely that any natural dimer could be obtained in this way (7). At this point it may be noted, however, that we were able to show subsequently that the desired C-16 -C-14 PARF relative stereochemistry can be obtained as a preferential result, albeit only in very low yield [3.6% PARF versus 2.1% PREF (priority reflective)], when the chloroindolenine reaction with vindoline is initiated with silver tetrafluoroborate (13). 

The real breakthrough toward synthesis of vinblastine and, in fact, the first significant laboratory preparation of binary indole-indoline alkaloids with the natural C-16 -C14 PARF configuration, was due to the work of the Potier-Langlois team at Gif (38,39 for reviews, see Refs. 40 and 41), buttressed by results obtained by the Kutney group in Vancouver (42,43,44), and the efforts of Atta-ur-Rahman and associates in Karachi. Their basic idea, which relied on the biogenetic consideration that binary indole-indoline alkaloids are formed in plants by the union of vindoline... 

Scheme 1. General biosynthetic pathway (a) for binary indole-indoline alkaloids such as vinblastine (1) and Potier s synthetic approach (b) based on that hypothesis.

Banwell MG, Lupton DW, Willis AC. Application of the palladium(0)-catalyzed Ullmann cross-coupling reaction in a total synthesis ( )-aspidospermidine and thus representing an approach to the lower hemisphere of the binary indole-indoline alkaloid vinblastine. Aus. J. Chem. 2005 58 722-737. 

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