alexa Antitumor Agents 291 Expanded B-Ring Modification Study of 6,8,8-Triethyl Desmosdumotin B Analogues as Multidrug-Resistance Selective Agents | OMICS International | Abstract
ISSN: 2161-0444

Medicinal Chemistry
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Research Article

Antitumor Agents 291 Expanded B-Ring Modification Study of 6,8,8-Triethyl Desmosdumotin B Analogues as Multidrug-Resistance Selective Agents

Kyoko Nakagawa-Goto1*, Kenneth F Bastow2, Emika Ohkoshi1, Susan L Morris-Natschke1 and Kuo-Hsiung Lee1,3*

1Natural Products Research Laboratories, EshelmanSchool of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

2Division of Medicinal Chemistry & Natural Products, EshelmanSchool of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA

3Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan

*Corresponding Author:
Dr. Nakagawa-Goto k
Natural Products Research Laboratories
EshelmanSchool of Pharmacy
University of North Carolina at Chapel Hill, Chapel Hill
North Carolina 27599, USA
Tel: 919-843-5209
Fax: 919- 966-3893
E-mail: [email protected]

Dr. KH Lee
Natural Products Research Laboratories
EshelmanSchool of Pharmacy
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina 27599, USA
Tel: 919-962-0066
Fax: 919-966-3893
E-mail: [email protected]

Received date: September 19, 2011; Accepted date: November 04, 2011; Published date: December 01, 2011

Citation: Nakagawa-Goto K, Bastow KF, Ohkoshi E, Morris-Natschke SL, Lee KH(2011) Antitumor Agents 291 Expanded B-Ring Modification Study of 6,8,8-Triethyl Desmosdumotin B Analogues as Multidrug-Resistance Selective Agents. Medchem 1:101. doi:10.4172/2161-0444.1000101

Copyright: © 2011 Uguroglu S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Drug usefulnessis frequently obstructed by the incidence of the multidrug resistance (MDR) phenotype and severe adverse effects. Exploiting collateral sensitive(CS)agents (in this case also called MDR-selective agents), which selectively target only MDR cells, is an emerging and novel approach to overcome MDR in cancer treatment. In prior studies, we found that 4’-methyl-6,6,8-triethyldesmosdumotin B (4’-Me-TEDB, 2) is an MDR-selective synthetic flavonoid with significant in vitro anticancer activity against a MDR cell line (KB-Vin) but without activity against the parent cells (KB) as well as other non-MDR tumor cells. Our recent results suggest the absolute MDR-selectivity varies depending on the cell-line system. In order to explore this further and to better understand the critical pharmacophores, we have synthesized nine novel analogues of 2, which contain heteroaromatic as well ascycloalkyl B-rings. The new compounds were evaluated for cytotoxicity to explore the effect of B-ring modifications on MDR-selectivity. All analogues, except 7, 9 and 10, were identified as significant MDR-selective compounds. This observation solidifies the importance of the 5-hydroxy-6,8,8-trialkyl-4H-chromene-4,7(8H)-dione skeleton (AC-ring system) for the pharmacological activity and establishes the B-ring as less critical for the broader spectrum MDR-selectivity. Notably, 3-furanyl (3)and 2-thiophenyl (6)analogues displayed substantial MDR–selectivity with KB/KB-Vin ratios of >12 and 16, respectively. Furthermore, 3 and 6 also exhibited MDR–selectivity in a second set of paired cell lines, theMDR/non-MDR hepatoma-cell system. Interestingly, a cyclohexyl analogue (11) showed moderate inhibition of A549, DU145, and PC-3 cell growth, while the other compoundswere inactive.These new findings are discussed in terms of current understanding of mechanism and structure–activity relationship (SAR) of our novel MDR-selective flavonoids.

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