Calophyllum Calanolides

Yet other compounds have been found to inhibit HIV-1 replication through a specific interaction with HIV-1 RT (i.e., quinoxaline S-2720 [68], 5-chloro-3-(phenylsulfonyl)indole-2-carboxamide [69], dihydrothiazolo-isoindolones [70] and a number of natural substances (e.g., calanolide A and inophyllums, from the tropical rain forest trees Calophyllum lanigerum and Calophyllum inophyllum, respectively) [71,72]. All these and yet other compounds could be considered to be NNRTIs. The most potent among the NNRTIs, some of the HEPT derivatives (E-EBU-dM) [63] and a-... 

Tropical rainforest tree and Malaysian tree A number of natural products have been reported to interact with reverse transcriptase, i.e., baicalin, avarol, avarone, psycho-trine, phloroglucinol derivatives and, in particular, calanolides (from the tropical rainforest tree, Calophyllum lanigerum) and inophyllums (from the Malaysian tree, Calophyllum inophyllum). 

Numerous dipyranocoumarins have been isolated from different species of Calophyllum. According to their chemical skeleton, they have three heterocycle rings, ring B, C, and D, constructed from a phloroglucinol core A. These compounds fall into three basic structural types (1) tetracycle dipyranocoumarins in which the D rings have a gem-dimethyl group, such as (-l-)-calanolide A (1), (-l-)-calanolide B... 

The chromeno-coumarin calanolide A, isolated from Calophyllum langiferum var. Austrocoriaceum, is nowadays in clinical trials as a nonnucleoside specific inhibitor of HIV-1 reverse transcriptase [64,65]. 

Several reviews have been published dealing with natural products-derived antiviral compounds [11,12,16-23]. Presently, there are only two plant-derived compounds under clinical development [2]. (+)-Calanolide A (12) is a C22 coumarin isolated from the Malaysian rainforest tree, Calophyllum langigerum by the U.S. National Cancer Institute [2]. It shows a potent HIV-RT inhibitory activity [2]. In vitro studies of 12 demonstrated activity against HIV-1 including AZT and other nonnucleoside RT inhibitors-resistant strains. It also shows synergistic anti-HIV activity in combination with nucleoside RT inhibitors 7, 8 and 9 [2]. To overcome the difficulty of supply of 12, its total chemical synthesis was accomplished [2]. In June 1997, clinical development of 12 was started as a potential drug for treatment of AIDS. A single -center 7-month U.S. phase la clinical trial of 12 was started to assess its safety and... 

Kashinan Y, Gustafson KR, Fuller RW, Cardellina JH, II, McMahon JB, Currens Ml, Buckheit RW, Hughes SH, Cragg GM, Boyd MR (1992) The Calanolides, a Novel HIV-inhibitory Class of Coumarin Derivatives from the Tropical Rainforest Tree, Calophyllum lanigerum. J Med Chem 35 2735... 

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