Camptothecin structure-activity relationships

In 1985, it was reported by Hsiang et al. [43] that the cytotoxic activity of 20-(S)-camptothecin (CPT III) was attributed to a novel mechanism of action involving the nuclear enzyme topo I, and this discovery of unique mechanism of action revived the interest in CPT and its analogues as anticancer agents. CPT stabilizes the covalent, reversible topo I-DNA complex leading to the inhibition of DNA synthesis in mammalian cells and interferes with the topo I breakage-reunion reaction [44]. Clinical trials and structure-activity relationships have demonstrated the requirement of the a-hydroxy group, the... 

Fig. 16.2 Structure-activity relationships for antitumor activity in camptothecins as known around 1995.

Marco, E., Laine, W., Tardy, C., Lansiaux, A., Iwao, M., Ishibashi, F., Bailly, C., Gago, F., (2005). Molecular determinants of topoisomerase I poisoning by lamellarins comparison with camptothecin and structure -activity relationships, J. Med. Chem. 48, 3796-3807. 

Since the initial isolation and structure determination of camptothecin in 1966 [1], numerous studies of the synthesis of analogues of this potent alkaloid have been carried out in order to define structure-activity relationships. The history of advances in camptothecin research may be divided into two... 

In order to summarize the structure-activity relationships of camptothecin analogues, we have divided the camptothecin molecule into four regions, i.e. north east (NE), north west (NW), south east (SE), and south west (SW) regions, and describe the distinctive features of each region. 

Yoon KJ-P, Krull EJ, Morton CL, Bommann WG, Lee RE, Potter PM, Danks MK (2003) Activation of a camptothecin prodrug by specific carboxylesterases as predicted by quantitative structure-activity relationship and molecular docking studies. Mol Cancer Ther 2 1171-1181... 

Camptothecin - An alkaloid from the tree CamPtotheca acuminata, camptothecln ( ) exhibits antineoplastic activity against the mouse leukemias, the plasma cell tumor YPC-1, Walker 256 rat carcinosarcoma and has cytotoxic activity against several cell lines.125-127 Total synthe-sisl28,129 and preliminary structure-activity relationship studiesl30 are reported. Camptothecin is not cross-resistant to leukemias made refractory to the antlfols, 6CNU, cytosine arabinoslde,... 

Fan Y, Shi LM, Kohn KW, Pommier Y, Weinstein JN. Quantitative structure-antitumor activity relationships of camptothecin analogues cluster analysis and genetic algorithm-based studies. J Med Chem 2001 44 3254-63. 

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