Drug design

3D-QSAR study of 20 (S)-camptothecin analogs

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Abstract

Aim:

To build up a quantitative structure-activity relationship (QSAR) model of 20 (S)-camptothecin (CPT) analogs for the prediction of the activity of new CPT analogs for drug design.

Methods:

A training set of 43 structurally diverse CPT analogs which were inhibitors of topoisomerase I were used to construct a quantitative structure–activity relationship model with a comparative molecular field analysis (CoMFA). The QSAR model was optimized using partial least squares (PLS) analysis. A test set of 10 compounds was evaluated using the model.

Results:

The CoMFA model was constructed successfully, and a good cross-validated correlation was obtained in which q2 was 0.495. Then, the analysis of the non-cross-validated PLS model in which r2 was 0.935 was built and permitted demonstrations of high predictability for the activities of the 10 CPT analogs in the test set selected in random.

Conclusion:

The CoMFA model indicated that bulky negative-charged group at position 9, 10 and 11 of CPT would increase activity, but excessively increasing bulky group at position 10 is adverse to inhibitory activity; substituents that occupy position 7 with the bulky positive group will enhance the inhibitive activity. The model can be used to design new CPT analogs and understand the mechanism of action.

References

  1. 1

    Wall ME, Wani MC, Cook CE, Palmer KH, McPhail AT, Sim GA . Plant antitumor agents I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from camptotheca acuminate. J Am Chem Soc 1966; 88: 3888–90.

  2. 2

    Tanizawa A, Fujimori A, Fujimori Y, Pommier Y . Comparison of topoisomerase I inhibition, DNA damage, and cytotoxicity of camptothecin derivatives presently in clinical trials. J Natl Cancer Inst 1994; 86: 836–42.

  3. 3

    Verweij J . Topoisomerase I inhibitors and other new cytotoxic drugs. Eur J Cancer 1995; 31: 828–30.

  4. 4

    Moertel CG, Schutt AJ, Reitemeier RJ, Hahn RG . Phase II study of camptothecin (NSC-100880) in the treatment of advanced gastrointestinal cancer. Cancer Chemother Rep 1972; 56: 95–101.

  5. 5

    Hsiang YH, Hertzberg R, Hecht S, Liu LF . Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 1985; 260: 14873–8.

  6. 6

    Cragg GM, Newman DJ . A tale of two tumor targets: topoisomerase I and tubulin. The Wall and Wani contribution to cancer chemotherapy. J Nat Prod 2004; 67: 232–44.

  7. 7

    SYBYL. Version 6.8. St Louis (MO): Tripos Associates; 2000.

  8. 8

    Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB, Stewart LJ . The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc Nat Acad Sci USA 2002; 99: 15387–92.

  9. 9

    Wall ME, Wani MC, Nicholas AW, Manikumar G, Tele C, Moore L, et al. Plant antitumor agents 30. Synthesis and structure activity of novel camptothecin analogs. J Med Chem 1993; 36: 2689–700.

  10. 10

    Carrigan SW, Fox PC, Wall ME, Wani MC, Bowena JP . Comparative molecular field analysis and molecular modeling studies of 20-(S)-camptothecin analogs as inhibitors of DNA topoisomerase I and anticancer/antitumor agents. J Comput Aided Mol Des 1997; 11: 71–8.

  11. 11

    Uehling DE, Nanthakumar SS, Croom D, Emerson DL, Leitner PP, Luzzio MJ, et al. Synthesis, topoisomerase I inhibitory activity, and in vivo evaluation of 11-azacamptothecin analogs. J Med Chem 1995; 38: 1106–18.

  12. 12

    Luzzio MJ, Besterman JM, Emerson DL, Evans MG, Lackey K, Leitner PL, et al. Synthesis and camptothecin antitumor activity of novel water soluble derivatives of camptothecin as specific inhibitors of topoisomerase I. J Med Chem 1995; 38: 395–401.

  13. 13

    Lackey K, Sternbach DD, Croom DK, Emerson DL, Evans MG, Leitner PL, et al. Water soluble inhibitors of topoisomerase I: quaternary salt derivatives of camptothecin. J Med Chem 1996; 39: 713–9.

  14. 14

    Bom D, Curran DP, Kruszewski S, Zimmer SG, Strode JT, Kohlhagen G, et al. The novel silatecan 7-tert-butyldimethylsilyl-10-hydroxycamptothecin displays high lipophilicity, improved human blood stability, and potent anticancer activity. J Med Chem 2000; 43: 3970–80.

  15. 15

    Thomas CJ, Rahier NJ, Hecht SM . Camptothecin: current perspectives. Bioorg Med Chem 2004; 12: 1585–604.

  16. 16

    Kim DK, Ryu DH, Lee JY, Lee N, Kim YW, Kim JS, et al. Synthesis and biological evaluation of novel A-ring modified hexacyclic camptothecin analogues. J Med Chem 2001; 44: 1594–602.

  17. 17

    Fan Y, Weinstein JN, Kohn KW, Shi LM, Pommier Y . Molecular modeling studies of the DNA-topoisomerase I ternary cleavable complex with camptothecin. J Med Chem 1998; 41: 2216–26.

  18. 18

    Yoon KJP, Krull EJ, Morton CL, Bornmann WG, Lee RE, Potter PM, et al. Activation of a camptothecin prodrug by specific carboxylesterases as predicted by quantitative structure-activity relationship and molecular docking studies. Mol Cancer Ther 2003; 2: 1171–81.

  19. 19

    Zhu J, Zhu W, Ji H, Zhou Y, Zhu J, Lü J . Comparative moleculer field analysis (CoMFA) of camptothecin analogs. Chin J Med Chem 1999; 9: 277–84.

  20. 20

    Cramer RD, Patterson DE, Bunce JD . Comparative molecular field analysis (CoMFA) 1. Effect of shape on binding of steroids to carrier proteins. J Am Chem Soc 1988; 110: 5959–67.

  21. 21

    Wold S, Albano C, Dunn WJ, Edlund U, Esbensen K, Geladi P, et al. Multivariate data analysis in chemistry. In: Kowalski B, editors. CHEMOMETRICS: Mathematics and statistics in chemistry. Dordrecht, Netherlands: Reidel; 1984.

  22. 22

    Stahle L, Wold S . Multivariate data analysis and experimental design in biomedical research. Prog Med Chem 1988; 25: 292–338.

  23. 23

    Esbensen KH, Wold S, Geladi P . Relationships between higher-order data array configurations and problem formulations in multivariate data analysis. J Chemometrics 1988; 3: 33–48.

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Correspondence to Hua-liang Jiang.

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Keywords

  • comparative molecular field analysis (CoMFA)
  • camptothecin (CPT)
  • topoisomerase I (Top I)

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