Anti-AIDS Agents. 37. Synthesis and Structure−Activity Relationships of (3‘R,4‘R)-(+)-cis-Khellactone Derivatives as Novel Potent Anti-HIV Agents

Abstract

To explore the structural requirements of (+)-cis-khellactone derivatives as novel anti-HIV agents, 24 monosubstituted 3', 4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) derivatives were synthesized asymmetrically. These compounds included 4 isomeric monomethoxy analogues (3-6), 4 isomeric monomethyl analogues (7-10), 4 4-alkyl/aryl-substituted analogues (11-14), and 12 4-methyl-(+)-cis-khellactone derivatives (15-26) with varying 3', 4'-substituents. These (+)-cis-khellactone derivatives were screened against HIV-1 replication in acutely infected H9 lymphocytes. The results demonstrated that the (3'R,4'R)-(+)-cis-khellactone skeleton, two (S)-(-)-camphanoyl groups at the 3'- and 4'-positions, and a methyl group on the coumarin ring, except at the 6-position, were optimal structural moieties for anti-HIV activity. 3-Methyl- (7), 4-methyl- (8), and 5-methyl- (9) 3',4'-di-O-(S)-camphanoyl-(3'R, 4'R)-(+)-cis-khellactone showed EC(50) and therapeutic index values of <5.25 x 10(-5) microM and >2.15 x 10(6), respectively, in H9 lymphocytes, which are much better than those of DCK and AZT in the same assay. Furthermore, 8 and 9 also showed potent inhibitory activity against HIV-1 replication in the CEM-SS cell line, and most monosubstituted DCK analogues were less toxic than DCK in both assays.

A Prenyloxycoumarin from Psiadia dentata.

“…1 H-NMR and HMBC (500 MHz) spectra were recorded in CDCl 3 using a FT Bruker DMX 500 WB spectrometer, 13 C-NMR (75 MHz) and NOESY (300 MHz) spectra were recorded in CDCl 3 using a FT Bruker AM 300 WB spectrometer; the chemical shifts (d) were given in ppm, coupling constants (J) were expressed in Hz, using tetramethylsilane (TMS) as internal standard. The LSI-MS mass spectra were obtained with a Varian MAT 311 mass spectrometer.…”

“…It was also evaluated, along with seselin, known to be a naturally occurring pyranocoumarin, for which some synthetic analogs exhibited potent in vitro anti-(HIV) activity. 13,14) Only a very weak effect (about 10% inhibition of HIV replication) was observed for these compounds with concentrations close to their cytotoxic concentration 50% (CC 50 ) on Sup T1 cells, i.e., 20 and 80 mg/ml for isoobtusitin and seselin, respectively.…”

“…4 H-decoupled and -coupled 13 C experiments, and the putative position of the various substituents on the aromatic ring was based on the comparison with known coumarins and with calculated values for d 13 C. 6) Directly C-H bonded carbons could be assigned by analysis of the gated decoupling 13 C spectrum ( Table 2). The doublets at d 6.2 and 7.95 (Jϭ9.7 Hz) were attributed to H-3 and H-4 and the deshielded nature of the latter proton suggested the presence of an oxygen function at the C-5 position.…”

“…Selective 1 H-irradiations followed by the observation of various modifications of the 13 Ccoupled NMR signals (Chart 1) led to the measurement of some informative x J C-H values (Table 2). For instance, we observed on the gated decoupling 13 C spectrum that the irradiation of CH 3 -9 at 3.90 simplified the signal at 131.8 ppm by suppression of the 3 J coupling through the O-bond. The irradiation at 6.44 caused a similar simplification of both multiplets at 131.8 and 102.4 ppm.…”

Natural Product‐Like Combinatorial Libraries

“…151 Based on the fact that many natural and designed benzopyrans that contain modifications of the pyran olefin exhibit higher and/or different activity than that of the parent molecule (ex. β-lapachone, (+)-kellactone) ( Figure 41), [162][163][164] the Nicolaou group 165 developed a solution-phase "library-from-library" strategy 166 in which the previous libraries were employed for further derivatization at the pyran olefin, thereby increasing the structural diversity.…”