Conclusions

Although the overall mechanism of action of topoisomerase inhibitors is well understood, there are yet few molecular-level details of the critical enzyme-drug-DNA ternary complexes that are formed. It is thus difficult to apply modern structural biology tools to the design of better agents. Nevertheless, this review shows that there is a vigorous research program into the development of new topoisomerase agents. This takes two general approaches.

In the absence of detailed structural biology, a major effort has gone into improving the broad deficiencies of established agents. In the topo I inhibitor class, several camptothecin analogs (exatecan, gimatecan, karenitecin) have lipophilic 7-substituents, providing compounds with enhanced membrane permeability as a way of counteracting cell efflux mechanisms. This may also provide better lactone stability (a major deficiency of camptothecin), as seen with karenitecin, by altering drug disposition. A more direct approach to the latter issue is seen in the homocamptothecin diflomotecan, where the 7-membered lactone ring is chemically more stable. All of these compounds show equal or superior potency to camptothecin, together with broad-spectrum activity and improved resistance to cell efflux mechanisms, and constitute an exciting set of potentially improved agents. For topo II inhibitors, a major drug design target is the cumulative cardiotoxicity shown by the key drug doxorubicin. The anthracycline/anthraquinone analogs discussed here address this in different ways, through more rapid extravascular diffusion and cell uptake (nemorubicin), differential tissue accumulation of the cardiotoxic alcohol metabolite (amrubicin), or lesser ability of this metabolite to bind to the critical enzyme (MEN-10755). Another issue, especially for the DNA-intercalating topo II agents, is to decrease their susceptibility to cell efflux pumps. This is not addressed as specifically by these compounds, with MEN-10755 in particular still susceptible to transport-mediated resistance.

The second major approach is to seek compounds with novel structures and mechanisms of action, although this is less apparent in the topo I field, where only the indolocarbazole edotecarin is reported on. This compound is more stable than previous indolocarbazole analogs, and active in P-gp-expressing cell lines. Overall, there is a much wider range of structures in the topo II inhibitor class, and many of these have the advantage of being generally not cardiotoxic, and usually lipophilic enough to avoid transport-mediated resistance (e.g., the pyridocarbazole S-16020-2, the pyrazoloacridone KW-2170, the indenoquinoline TAS-103). Many of these compounds appear to inhibit topo II in different ways to the anthracyclines, and some may act by additional mechanisms (e.g., selective accumulation in lung tissue via phosphatidylserine binding by the podophyllotoxin derivative TOP-53, hydroxyl radical-induced oxidative cleavage of DNA by the chartreusin analog IST-622). In general, more work on the mechanisms of action of these compounds would be beneficial.

The dual topo I/II inhibitors represent the newest class of topoisomerase-active drugs. While it is still not clear how viable the original rationale (resistance to one class of inhibitors resulting in an increase in level of the other enzyme) is for seeking such compounds, the class has given rise to some interesting examples. The homocamptothecin BN-80927, the etoposide tafluposide, and the chartreusin analog elsamitrucin pose interesting questions about the properties needed to convert a topo I or II inhibitor to a dual one, and vice versa. More work is needed to explore this area. Some of the compounds (e.g., tafluposide, elsamitrucin, XR-11576) appear to inhibit topoisomerase in a novel manner, and some (e.g., MLN-944) may in fact work primarily by nontopo mechanisms.

Overall, the work reviewed here indicates that the field is still developing vigorously, with a variety of specific new drug design approaches being followed.

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Biography

William A Denny was trained at the universities of Auckland and Oxford as a medicinal chemist, and is the Director of the Auckland Cancer Society Research Centre in the Medical School of the University of Auckland. He is a founding scientist of Proacta Therapeutics Ltd, a biotechnology company focused around the development of hypoxia-activated drugs for cancer therapy. He is a past President of both the NZ Society for Oncology and the NZ Institute of Chemistry, and was the 2005 Adrien Albert Medallist of the UK Royal Society of Chemistry. He has been closely involved in the design and development of nine new cancer drugs to clinical trials in NZ, the USA, and Europe, and is author of about 530 scientific papers and 75 patent applications.

© 2007 Elsevier Ltd. All Rights Reserved Comprehensive Medicinal Chemistry II

No part of this publication may be reproduced, stored in any retrieval system or transmitted ISBN (set): 0-08-044513-6 in any form by any means electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publishers ISBN (Volume 7) 0-08-044520-9; pp. 111-128

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