Total Synthesis and Biological Evaluation of the Potent HIV Latency-Reversing Agent Ansellone A and its Analogues

Abstract

The total synthesis and biological evaluation of the marine sesterterpenoid ansellone A (1), an HIV latency-reversing agent, and its analogues are reported. The key to the success of this synthetic route is a Prins cyclization reaction enabled by the strategic use of the TfO group for stabilization of the acid-labile tertiary allylic alcohol. The SAR study found the alcohol analogue to exhibit more potent activity than 1.

Ansellone J, a Potent in Vitro and ex Vivo HIV-1 Latency Reversal Agent Isolated from a Phorbas sp. Marine Sponge

“…As part of the original structure elucidation of ansellone A ( 2 ), the natural product had been hydrolyzed and the resulting allylic alcohol was crystallized and subjected to X-ray diffraction analysis . Ansellone J ( 6 ) has recently been synthesized as part of a synthetic study of ansellone A ( 2 ) and analogues, but this is the first report of 6 as a natural product …”

“…8 Ansellone J (6) has recently been synthesized as part of a synthetic study of ansellone A (2) and analogues, but this is the first report of 6 as a natural product. 11 Ansellone K ( 7) was isolated as a white powder. It gave an [M + Na] + ion peak in the ESITOFHRMS spectrum at m/z 437.2666, which was consistent with a molecular formula of Table 1.…”

Exploring Chemical Diversity of <em>Phorbas</em> Sponges as a Source of Novel Lead Compounds in Drug Discovery

“…The compounds alotaketal C (62) and D (63) and anvilone A were reported to activate the latent proviral HIV-1 gene expression. Notably, alotaketal C (62) was more potent and gave a stronger effect than the control compound prostratin at the same concentration, while alotaketal D (63) and anvilone A elicited similar responses as prostratin [52,77,78].…”

“…Recently a dereplication study, based upon comparison of HR-MS fragmentation pathways, allowed the annotation of 18 known Phorbas metabolites, for the extract of P. amaranthus, collected in Brazil. Among the known compounds are: phorbasins (87-89, 90-92, 93-95, 96-100), phorbaketals (45)(46)(47)49), isophorbasone (78), ansellones (72), anvillones (80) and phorbasterones (34)(35)(36)(37)(38)(39) [67].…”

“…cAMP signaling activation by ansellone A (65) was comparable to that of forskolin, a natural product used for the treatment of cancer, obesity and allergies [53]. The latency reversal activity (LRA) of 65, which has the function of reactivate the virus production in infected cells and produce an immune response or cell death, was also reported and determined by quantification of the changes in intracellular GFP expression in microplate [78]. The sesterterpenoid ansellone B (66) was reported as a potent inhibitor on nitric oxide production in RAW 264.7 LPS-activated mouse macrophage cells [79].…”