Seco-cyclic phorbol derivatives and their anti-HIV-1 activities

Abstract

Phorbol esters are recognized for their dual role as anti-HIV-1 agents and as activators of protein kinase C (PKC). The efficacy of phorbol esters in binding with PKC is attributed to the presence of oxygen groups at positions C20, C3/C4, and C9 of phorbol. Concurrently, the lipids located at positions C12/C13 are essential for both the anti-HIV-1 activity and the formation of the PKC-ligand complex. The influence of the cyclopropane ring at positions C13 and C14 in phorbol derivatives on their anti-HIV-1 activity requires further exploration. This research entailed the hydrolysis of phorbol, producing seco-cyclic phorbol derivatives. The anti-HIV-1 efficacy of these derivatives was assessed, and the affinity constant (K_d) for PKC-δ protein of selected seco-cyclic phorbol derivatives was determined through isothermal titration calorimetry. The findings suggest that the chemical modification of cyclopropanols could affect both the anti-HIV-1 activity and the PKC binding affinity. Remarkably, compound S11, with an EC50 of 0.27 μmol·L⁻¹ and a CC₅₀ of 153.92 μmol·L⁻¹, demonstrated a potent inhibitory effect on the intermediate products of HIV-1 reverse transcription (ssDNA and 2LTR), likely acting at the viral entry stage, yet showed no affinity for the PKC-δ protein. These results position compound S11 as a potential candidate for further preclinical investigation and for studies aimed at elucidating the pharmacological mechanism underlying its anti-HIV-1 activity.

Keywords

seco-Cyclic phorbol derivatives / Hydrolysis reaction / Cyclopropane ring / Esterification / Anti-HIV-1 agent

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Funding

National Natural Science Foundation of China(81202882)

National Natural Science Foundation of China(82060670)

Suzhou Science and Technology Planning Project in Jiangsu Province of China(SNG2021022)

Priority Academic Program Development of the Jiangsu Higher Education Institutes, China(PAPD)

Project of Innovative Research Team of Yunnan Province(202005AE160005)