HIV-1 integrase inhibitors that block HIV-1 replication in infected cells. Planning synthetic derivatives from natural products
R. Di Santo, R. Costi, M. Artico, E. Tramontano, P. La Colla, and A. Pani
1Istituto Pasteur—Fondazione Cenci Bolognetti, Dipartimento
di Studi Farmaceutici (Dip. 63), Università di Roma “La
Sapienza”, Piazzale A. Moro 5, I-00185 Roma, Italy; 2Dipartimento
di Biologia Sperimentale, Sezione di Microbiologia, Università
di Cagliari, Cittadella Universitaria, SS 554, I-09042 Monserrato, Cagliari,
Italy
Abstract: Combination therapy using reverse transcriptase
(RT) and protease (PR) inhibitors is currently the best clinical approach
in combatting acquired immunodeficiency syndrome (AIDS), caused by infection
from the human immunodeficiency virus type 1 (HIV-1). However, the emergence
of resistant strains calls urgently for research on inhibitors of further
viral targets such as integrase (IN), the enzyme that catalyzes the
integration of the proviral DNA into the host chromosomes. Recently,
we started studies on new IN inhibitors as analogs of natural products,
characterized by one or two 3,4-dihydroxycinnamoyl moieties, which were
proven to be IN inhibitors in vitro. Then, we designed and synthesized
a number of derivatives sharing 3,4 dihydroxycinnamoyl groups, obtaining
potent IN inhibitors active at submicromolar concentrations. Unfortunately,
these derivatives lacked antiretroviral activity, probably owing to
their high cytotoxicity. So we designed a number of 3,4,5-trihydroxycinnamoyl
derivatives as less-cytotoxic IN inhibitors, which were proven to be
antiretrovirals in cell-based assays. Finally, we designed and synthesized
a number of aryldiketohexenoic acids, strictly related to the aryldiketo
acid series recently reported by Merck Company, which were shown to
be potent antiretroviral agents endowed with anti-IN activities either
in 3' processing or in strand transfer steps.
*Pure Appl.Chem. 75,
141�419 (2003). An issue of reviews and research papers based on
lectures presented at the 23rd IUPAC International Symposium on the
Chemistry of Natural Products, Florence, Italy, 28 July � 2 August 2002.
