Numerous plant-derived compounds have been evaluated for inhibitory effects against HIV replication, and some coumarins have been found to inhibit different stages in the HIV replication cycle. This review article describes recent progress in the discovery, structure modification, and structure-activity relationship studies of potent anti-HIV coumarin derivatives. A dicamphanoyl-khellactone (DCK) analog, which was discovered and developed in our laboratory, and calanolide A are currently in preclinical studies and clinical trials, respectively.

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A series of coumarins and related compounds were synthesized and screened as potential anti-tumor-promoting agents by examining the ability of the compound to inhibit Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. The most promising compound in this in vitro assay, 7,8-di(3-methyl-2-butenyloxy)coumarin (17), showed confirmed chemopreventive activity in an in vivo two-stage assay of mouse skin tumors (DMBA=TPA). TPA). This investigation also confirmed an important role for the prenyl moiety, and, possibly, for the dimethylpyran substructure, on the anti-tumor-promoting activity.

ABSTRACT:3,4-Di-O-(؊)-camphanoyl-(؉)-cis-khellactone (DCK) is a synthetic khellactone ester that exhibits potent in vitro anti-human immunodeficiency virus (HIV) activity with a mechanism distinct from clinically used anti-HIV agents. Several series of mono-and di-substituted DCK derivatives (DCKs) have previously been synthesized, and their structure-activity relationships are well established. To optimize DCK as a drug lead and to guide further structural modifications, metabolic stabilities and metabolite structures were analyzed. In vitro metabolic stabilities of DCKs in human liver microsomes were assessed using high performance liquid chromatography (HPLC) with UV detection to establish structure-metabolism relationships (SMRs). HPLC coupled with ion trap mass spectrometry was used to identify the metabolite structures. The results indicated that DCKs undergo rapid oxidation on the lipophilic camphanoyl moieties and the substituents on the khellactone do not alter the rate or the metabolic pathways for this compound type. Our SMR and metabolite analysis study suggested that the two camphanoyl ester moieties are the determinants of the low metabolic stability and that structural alteration in the two esters may be necessary to improve metabolic profiles of DCKs. Fig. 1) is a natural product derivative with potent anti-HIV activity and a distinct mechanism of antiviral action (Huang et al., 1994). Over 20 derivatives of DCK (DCKs) have been synthesized to optimize the activity, some with EC 50 values in the nanomolar range and high therapeutic indexes (Takeuchi et al., 1997;Xie et al., 1999Xie et al., , 2001Xie et al., , 2004. The DCK structure consists of a modified khellactone ring system and two camphanoyl ester moieties. Modifications of the khellactone ring greatly affect the in vitro activity, dependent both on the position and type of the substituents (Yu et al., 2003). Preliminary in vivo studies of several DCKs in rats indicated low oral bioavailability (0 -15%) and high clearance value close to the liver blood flow, corresponding to rapid in vitro metabolism by rat liver microsomes. Although absorption may also be an issue, the comparison of calculated log D values with the bioavailability indicated that it is not the only factor for the differences (Xie et al., 2004). These results prompted an evaluation of how the structure can influence metabolism of the DCKs. The study was based on the hypothesis that we can select or design a DCK analog with improved bioavailability by obtaining information about metabolic properties of the available DCKs. The objectives were 1) to investigate the metabolic stability of various DCKs in human liver microsomes using HPLC-UV, establish structure-metabolism relationship (SMR) correlations, and identify a possible structural motif and/or position that could provide improved stability; 2) to determine the positions (3Ј or 4Ј) of fragmentations of khellactone esters under MS/MS mode using structural analogs; and 3) to determine the sites of oxidative metabolism by an...

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