Research Synopsis

Plant-derived chemical probes and privileged templates, natural product drug discovery, exploiting collateral sensitivity and P-glycoprotein abuse

Research Interests

Antitumor chemical biology work is two-pronged, focusing on phytochemicals as potential drug leads and privileged scaffolds and as tools to test hypothesis about tumor-cell biology and about the biochemical pharmacology of novel agents. Medicinal chemistry aspects are largely done in conjunction with the Natural Product Laboratories as part of a long-term NIH-funded collaboration with K.H. Lee, PhD. Isolation of active ingredients using a combination of traditional in vitro anticancer assay and target-based selection has led to more than 160 joint publications. The specific research focus and interests noted above is best exemplified by the example of new initiatives around Dastrichone (Desmosdumotin B, 1; see chemical structure below).

Fig 1:Diagram spotlighting research activity and testable hypothesis around referenced bioactive flavonoids: three scenarios involving change in the P-glycoprotein target are depicted (1=simple up-regulation; 2 = enzyme biochemical change; 3 = change in context and partnering; note that 1-3 are not mutually exclusive)

This bioflavonoid is a specific cytotoxic agent that selectively kills several multidrug-resistant cancer (MDR) cell lines overexpressing functional human P-glycoprotein (P-gp). ^108,131.One can say that MDR-1 cancer cell lines have a predilection for the P-gp enzyme and this abuse imparts collateral sensitivity to 1 and active analogs. The P-gp dependent action leading to collateral sensitivity occurs within two hours, and the margin of hypersensitivity (i.e. the CS index) increases following pre-exposure or selection using a commonly used cancer drug. We have also discovered that P-gp abuse can lead to addiction, and P-gp abuse is targeted by phytochemicals other than flavonoids. ^{142, unpublished} Therefore it is interesting to know whether the latter connection has any biological significance as MATE-type ABCB proteins are known to play complex roles in plant growth and development, and their function is modulated by plant metabolites.

With respect to the in vitro anticancer mechanism, three possible scenarios involving P-gp in the hypersensitive cell line are shown in Figure 1; current efforts have led to a clear definition of structure-activity relationships around 1 and have also provided intriguing insights into a mode of action consistent with the third scenario (Fig 1). ^151,167 Interestingly replacing the phenyl B-ring of 1 with certain bicyclic moieties (for example benzo[b] thiophenyl, 2), affords tubulin-targeting agents with modest or no MDR-selectivity. However, cytotoxic action is not impacted by MDR-1 and 2 exhibits broad-spectrum and 100-to-200-fold higher in vitro anticancer activity. ¹⁶² Thus the 5-hydroxy-6,8,8-trialkyl-4H-chromene-4,7(8H)-dione substructure of 1 confers interesting properties on experimental drugs depending on the type and substitution pattern of ring B.

Big gaps in knowledge concern molecular target interaction and mechanism as well as potential for moving cancer therapy forward. Advancing understanding of significant questions of tumor cell biology, like the molecular basis of the MDR-CS phenomenon and promoting the discovery and preclinical development of lead compounds like 1 and 2, highlight the general thrust of future studies. Scope of research interest extends to herpes virus biology and antiviral drug discovery as well as drug discovery around validated drug targets.

Please refer to the curriculum vitae for a complete accounting and for the specific references cited.

Ten Most Recent Publications as Corresponding Author

1. Cytotoxic esterified diterpenoid alkaloid derivatives with increased selectivity against a drug-resistant cancer cell line. Wada K, Ohkoshi E, Morris-Natschke SL, Bastow KF, Lee KH. Bioorg Med Chem Lett. 2012 Jan 1;22(1):249-52. Epub 2011 Nov 11. PMID: 22142543 [PubMed - in process]

2. Bis-chalcone analogues as potent NO production inhibitors and as cytotoxic agents. Vijaya Bhaskar Reddy M, Shen YC, Ohkoshi E, Bastow KF, Qian K, Lee KH, Wu TS. Eur J Med Chem. 2012 Jan;47(1):97-103. Epub 2011 Oct 20. PMID: 22115618 [PubMed - in process]

3.Antitumor agents 288: design, synthesis, SAR, and biological studies of novel heteroatom-incorporated antofine and cryptopleurine analogues as potent and selective antitumor agents. Yang X, Shi Q, Yang SC, Chen CY, Yu SL, Bastow KF, Morris-Natschke SL, Wu PC, Lai CY, Wu TS, Pan SL, Teng CM, Lin JC, Yang PC, Lee KH. J Med Chem. 2011 Jul 28;54(14):5097-107. Epub 2011 Jun 28. PMID: 21668000 [PubMed - indexed for MEDLINE]

4. Cytotoxic geranylflavonoids from Bonannia graeca. Rosselli S, Bruno M, Maggio A, Raccuglia RA, Safder M, Lai CY, Bastow KF, Lee KH. Phytochemistry. 2011 Apr 1. [Epub ahead of print] PMID: 21459391 [PubMed - as supplied by publisher]

5. Antitumor agents 287. Substituted 4-amino-2H-pyran-2-one (APO) analogs reveal a new scaffold from neo-tanshinlactone with in vitro anticancer activity. Dong Y, Nakagawa-Goto K, Lai CY, Morris-Natschke SL, Bastow KF, Lee KH. Bioorg Med Chem Lett. 2011 Apr 15;21(8):2341-4. Epub 2011 Mar 21. PMID: 21420855 [PubMed - indexed for MEDLINE]

6. Bioactive constituents from the roots of Panax japonicus var. major and development of a LC-MS/MS method for distinguishing between natural and artifactual compounds. Chan HH, Hwang TL, Reddy MV, Li DT, Qian K, Bastow KF, Lee KH, Wu TS. J Nat Prod. 2011 Apr 25;74(4):796-802. Epub 2011 Mar 18. PMID: 21417387 [PubMed - indexed for MEDLINE]

7. New bichalcone analogs as NF-κB inhibitors and as cytotoxic agents inducing Fas/CD95-dependent apoptosis. Reddy MV, Shen YC, Yang JS, Hwang TL, Bastow KF, Qian K, Lee KH, Wu TS. Bioorg Med Chem. 2011 Mar 15;19(6):1895-906. Epub 2011 Mar 4. PMID: 21377368 [PubMed - indexed for MEDLINE]

8. A unique P-glycoprotein interacting agent displays anticancer activity against hepatocellular carcinoma through inhibition of GRP78 and mTOR pathways. Kuo TC, Chiang PC, Yu CC, Nakagawa-Goto K, Bastow KF, Lee KH, Guh JH. Biochem Pharmacol. 2011 May 1;81(9):1136-44. Epub 2011 Mar 1. PMID: 21371443 [PubMed - indexed for MEDLINE]

9. Antitumor agents 283. Further elaboration of desmosdumotin C analogs as potent antitumor agents: activation of spindle assembly checkpoint as possible mode of action. Nakagawa-Goto K, Wu PC, Bastow KF, Yang SC, Yu SL, Chen HY, Lin JC, Goto M, Morris-Natschke SL, Yang PC, Lee KH. Bioorg Med Chem. 2011 Mar 1;19(5):1816-22. Epub 2011 Jan 15. PMID: 21296579 [PubMed - indexed for MEDLINE]

10. Antitumor agents. 284. New desmosdumotin B analogues with bicyclic B-ring as cytotoxic and antitubulin agents. Nakagawa-Goto K, Wu PC, Lai CY, Hamel E, Zhu H, Zhang L, Kozaka T, Ohkoshi E, Goto M, Bastow KF, Lee KH. J Med Chem. 2011 Mar 10;54(5):1244-55. Epub 2011 Feb 1. PMID: 21284385 [PubMed - indexed for MEDLINE]