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

Abstract

Five new minor sesterterpenoids, ansellones H (4), I (5), J (6), and K (7) and phorone C (8), have been isolated from a Phorbas sp. marine sponge collected in British Columbia. Their structures have been elucidated by detailed analysis of NMR and MS data. Ansellone J ( 6) and phorone C (8) are potent in vitro HIV-1 latency reversal agents that are more potent than the reference compound and control protein kinase C activator prostratin (3). The most potent Phorbas sesterterpenoid, ansellone J ( 6), was evaluated for HIV latency reversal in a primary cell context using CD4+ T cells obtained directly from four combination antiretroviral therapy-suppressed donors with HIV. To a first approximation, ansellone J (6) induced HIV latency reversal at levels similar to prostratin (3) ex vivo, but at a 10-fold lower concentration.

Synthesis and Biological Evaluation of Simplified Ansellone Analogues with Lipophilic Side Chains as HIV Latency‐Reversing Agents

“…Ansellone A and J have been reported to exhibit HIV latency‐reversing activity via activation of PKC [4,13] . Therefore, it is likely that a series of simplified analogues 4 also exhibit activity through a similar mechanism of action.…”

“…Ansellone A and J have been reported to exhibit HIV latencyreversing activity via activation of PKC. [4,13] Therefore, it is likely that a series of simplified analogues 4 also exhibit activity through a similar mechanism of action. To clarify whether PKC activation triggers latency-reversing activation, we investigated the effect of PKC inhibitors on the activity of the selected compounds 4 i and 4 j (Figure 9).…”

Discovery of New Cytotoxic Aplaminone Derivatives from the Sea Hare Aplysia kurodai and Elucidation of Their Accumulation from Local Sea Algae through the Food Chain

“…This activity was established for aplyronine C, a minute congener of aplyronine A that lacks microtubule disassembly activity, despite exhibiting the same actin‐depolymerizing activity. Therefore, investigation of minor substances, even in the case of well‐studied organisms, might lead to the discovery of new compounds with significant biological activities and structural novelty, and to a better understanding of their biosynthetic and metabolic pathways [14–17] …”

“…Therefore, investigation of minor substances, even in the case of well-studied organisms, might lead to the discovery of new compounds with significant biological activities and structural novelty, and to a better understanding of their biosynthetic and metabolic pathways. [14][15][16][17] Over the past few years, an innovative method for comprehensive analysis of non-targeted mass spectrometry data, namely "molecular networking analysis", has been developed. [18][19][20] This technique allows us to easily categorize structurally similar compounds as a "molecular family" based on MS/MS spectral similarity and to dereplicate known compounds by a search of the Global Natural Product Social Molecular Networking (GNPS) spectral library.…”

Total Synthesis of Ansellone G and Phorbadione

“… They have unique structures, in which the hydrobenzopyran skeleton is combined with different oxidized decalin skeletons. Some of these natural products reportedly exhibit interesting biological activities, such as cAMP activating ability and HIV latency-reversing activity, which can be used in the shock and kill method to cure HIV . Therefore, developing a method for the comprehensive synthesis of ansellanes is significant for further biological investigation.…”