Ellipticine analogs

Photolysis of the 1-aryltriazolopyridines 292 gives an ellipticine analog (see also Section IV,F).179... 

Most of the new synthetic work on ellipticine in the late 1980s has dealt with modified ellipticine derivatives. Several French groups have made enormous strides in the design and synthesis of ellipticine analogs. The material in this section is divided into nine areas A. Synthesis of Substituted Ellipticines B. Synthesis of Isoellipticines C. Synthesis of Azaellipticines D. Synthesis of Nonlinear Pyridocarbazoles E. Synthesis of Oxazolopyridocarbazoles F. Syn-... 

Although the exploration of novel ellipticine analogs continued in the late 1980s, in general, the further one deviates from the fundamental ellipticine structure, the less will be the antitumor activity. This section delineates a potpourri of such analogs. 

The cytotoxicity of several benzo-annulated iso-a-carbolines (369-372, 377, 378, 380) has been studied in vitro on human tumor KB cells (Table X) 136). The linear ellipticine analog 371 is 10 times more active than ellipticine (1) in this screen. As was mentioned earlier, this derivative also displays significant in vivo activity against P388, L1210, and B16 implanted mouse tumors TIC values 190, 175, and 224%, respectively). The resemblance of the imine grouping of these iso-a-carbolines to ellipticine quinone imine 6 is obvious. It will be of interest to see how the electrophilic behavior of these compounds compares to that of the quinone imines. 

Shi LM, Myers TG, Fan Y et al. Mining the National Cancer Institute Anticancer Drug Discovery Database Cluster analysis of ellipticine analogs with p53-inverse and central nervous system-selective patterns of activity. Mol Pharmacol 1998 53 241-51. 

The total synthesis of ellipticine by Miller el al. [11] is one of the first syntheses of naturally occurring indole alkaloids using Pd(OAc), via the oxidative cyclization mechanism (Scheme 2). Exposure of 6-anilino-5,8-dimethylisoquinoline (9) to two equivalents of Pd(OAc)j in TFA/AcOH facilitated the oxidative cyclization to the desired ellipticine (10). Recently, the same indole formation strategy that uses the Pd(OAc),-mediated oxidative cyclization has been the cornerstone of several synthetic approaches directed toward ellipticine analogs. For instance, oxidative cyclization of diphenylamine 11 was carried out with Pd(OAc), in acetic acid to provide... 

Another use of the indolylborate reagent (69) was reported in the total synthesis of ellipticine analogs by the Ishikura group [46]. As illustrated in Scheme 14, vinylbromide 75 and indolylborate 69 underwent a tandem intramolecular Heck-Suzuki reaction to give hexatriene 76 which was then converted to the desired pyrido(4,3-hlcarbazoie 77 using the well-known photocyclization protocol for styrylindole systems. 

Scheme 14. Total synthesis of ellipticine analogs using indolylboronate...

Popp FD, Veeraraghavan S 1982 Synthesis of potential antineoplastic agents. XXVII. (Reissert compound studies. XLIV.). The ellipticine Reissert compounds as an intermediate in the syntheses of ellipticine analogs. J Heterocycl Chem 19 1275-1280... 

An analogous sequence to that described for ellipticine was used to convert 5-methoxyindole (1171) to 9-methoxyellipticine (229). Noteworthy is the fact that none of the other regioisomeric keto acid could be detected by analysis of the crude product 1177. Using this sequence, 9-methoxyellipticine (229) was obtained in 47% overall yield based on 1171. O-Demethylation of 9-methoxyellipticine (229)... 

Among the carbazole alkaloids the most noteworthy is ellipticine (28). It and a number of synthetic analogs exhibit significant antitumor activity. The mechanism of action is believed to involve interaction with DNA (79MI30602). 

This chapter deals with the synthesis and biological properties of the relatively small family of pyrido[4,3- lcarbazole alkaloids, exemplified by ellipticine (1), 9-methoxyellipticine (2), 9-hydroxyellipticine (3), and olivacine (4), and of the much larger number of structural analogs that have been synthesized and studied... 

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