Anti-HIV-1 activity of calanolides

Flavin et al. reported on the anti-HTV-1 activity of synthetic ( )-calanolide A and resolved (-l-)-calanolide A (1) and ( )-calanolide A [( )- ] against both strains and clinical isolates of HTV-l shown in Table 8-1. The cytotoxicity in the different ceU lines examined of the ( )-l, (+)-l, and ( )-calanolide A was approximately the same levels. However, only (+)-l exhibited HTV-l activity, which was similar to the data reported for the namral product [(+)-calanolide A, (1)], and ( )-l was inactive. Both the AZT-resistant strain G910-6 and the pyridinone-resistant strain A17 were inhibited by ( )-l and (-T)-l. The (-T)-l was more active than ( )-I against the AZT-resistant strain G910-6 with an EC50 value of 0.027 and 0.108 pM, respectively. It was interesting that the activity of ( )-l 

TABLE 8-2. Antiviral Activity of ( )-, (+)-, and ( )-12-Oxo-calanolide A (3) Against Varions Infected CEM-SS Cells 

2 Anti-HIV-1 Activity of Calanolides in Hollow Fiber Mouse Evaluation of (-l-)-calanolide A (1) in a hollow fiber culture-based in a SCID mouse assay of antiviral efficacy indicated that (+)-calanolide A exhibited significant anti-HIV-1 activity after oral or parenteral administration on a once-daily (200mg/kg/ dose) or twice-daily (150 mg/kg/dose) treatment. Furthermore, a synergistic effect was observed in the combination of (-l-)-calanolide A and AZT.  

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Buchheit, R. W Jr Russell, J. D. Xu, Z. Q. Flavin, M. Anti-HIV-1 activity of calanolides used in comhination with other mechanistically diverse inhibitors of HIV-1 replication. Antiviral Chem. Chemother., 2000, 11 321-327. 

Quite recently, the use of natural cinchona alkaloids as catalysts for the intramolecular oxo-Michael addition of o-tigloylphenol (3), furnishing chiral ris-2,3-dimethyl-4-chromanone 4, which is a valuable intermediate for the synthesis of the anti-HIV-1 active coumarins, (+ )-calanolide A (5a), and (+ )-inophyllum B (5b), was reexamined by Ishikawa and coworkers (Scheme 9.2) [2], The parent cinchona alkaloids,... 

Roush WR, Hall SE (1981) Studies on the total synthesis of chlorothricol-ide stereochemical aspects of the intramolecular Diels-Alder reactions of methyl undeca-2,8,10-trienoates. J Am Chem Soc 103 5200-5211 Rudler H, Denise B, Xu Y, Parlier A, Vaissermann J (2005) Bis(trimethylsilyl)-ketene acetals as C,0-dinucleophiles one-pot formation of polycyclic y-and 8-lactones from pyridines and pyrazines. Eur J Org Chem 3724-2744 Sekino E, Kumamoto T, Tanaka T, Ikeda T, Ishikawa T (2004) Concise synthesis of anti-HIV-1 Active (+)-inophyllum B and (+)-calanolide A by application of (-)-quinine-catalyzed intramolecular oxo-michael addition. J Org Chem 69 2760-2767... 

Some structural modihcations of (+)-calanohde A or (-)-calanolide B have been carried out. However, no compounds showed anti-HIV-1 activity superior to the two lead compounds (1 and 15). Hopefully, calanolide A continues to have promise as an anti-HIV drug in the near future. 

Sekino, E. Kumamoto, T. Tanaka, T. Ikeda, T. Ishikawa, T. Concise synthesis of anti-HIV-1 active (-l-)-inophyllum B and (-l-)-calanolide A by application of (—)-quinine-catalyzed intramolecular oxo-Michael addition. J. Org. Chem., 2004, 69 2760-2769. 

Sekino E, Kumamoto T, Tanaka T, Ikeda T, Ishikawa T (2004) Concise Synthesis of Anti-HIV-1 Active (+)-Inophyllum B and (-t)-Calanolide A by Application of (-)-Quinine-Catalyzed Intramolecular Oxo-Michael Addition. J Org Chem 69 2760... 

Between 1987 and 1996, the NCI tested over 30 000 plant extracts in an in vitro cell-based anti-HIV screen (http //www.niaid.nih.gov), which determined the degree of HIV-1 replication in treated infected lymphoblastic cells versus that in treated uninfected control cells. Several natural products showed in vitro activity and michellamine B, the calanolides, and prostratin are discussed below. 

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... 

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