Synthesis and Structure-Activity Relationship Correlations of Gnidimacrin Derivatives as Potent HIV-1 Inhibitors and HIV Latency Reversing Agents

Abstract

Currently, due to the HIV latency mechanism, the search continues for effective drugs to combat this issue and provide a cure for AIDS. Gnidimacrin activates latent HIV-1 replication and inhibits HIV-1 infection at picomolar concentrations. This natural diterpene was able to markedly reduce the latent HIV-1 DNA level and the frequency of latently infected cells. Therefore, gnidimacrin is an excellent lead compound, and its anti-HIV potential merits further investigation. Twenty-nine modified gnidimacrin derivatives were synthesized and evaluated in assays for HIV replication and latency activation to establish which molecular structures must be maintained and which can tolerate changes that may be needed for better pharmacological properties. The results indicated that hydroxyl substituents at C-5 and C-20 are essential, while derivatives modified at 3-OH with aromatic esters retain anti-HIV replication and latent activation activities. The half-lives of the potent GM derivatives are over 20 h, which implies that they are stable in the plasm even though they contain ester linkages. The established structure-activity relationship should be useful in the development of gnidimacrin or structurally related compounds as clinical trial candidates.

Figure 1.

Strategy for modification of anti-HIV lead gnidimacrin.

Figure 2.

Enzastaurin abrogated the anti-HIV-1 activity of GM (1) and 13e. The effects of 1 or 13e on HIV-1 NL4-3 NanoLuc-sec infection of MT4 cells were determined in the presence or absence of enzastaurin. The 100% control in the y axis denotes HIV-1 replication in the absence of any compounds. The assays were performed in the presence of 0.6 nM 1 (blue bars), 2 nM 13e (orange bars), or without any PKC agonists (NA, gray bars). Enz-0, Enz-1 μM, and Enz-1/3 μM in the x axis represent the experimental groups with enzastaurin at 0 μM, 1 μM, and 1/3 μM, respectively. The data shown in the figure were derived from a duplicated antiviral assay.

Figure 3.

SAR correlations of derivatives of 1.

Scheme 1.. Synthesis of 2–6^a

^aReagents and conditions: (a) acetic anhydride, pyridine, 40 °C, overnight (60% yield); (b) benzyl chloride, pyridine, rt, overnight (100% yield); (c) K₂CO₃, MeOH, reflux (39% yield); (d) K₂CO₃, MeOH, rt (81%yield); (e) Pd/C, EtOAc, rt, 4 h (67% yield).

Scheme 2.. Synthesis of GM Derivatives 9a–9h^a

^aReagents and conditions: (a) bis(trifluoromethanesulfonic acid), pyridine, 0°C, 1 h (25% yield) (b) Dess-Martin periodinane, DCM, rt, 6 h/acetic/tiglic anhydride, DMAP, pyridine, 40°C, 4 h or 7 days/corresponding acid chloride, pyridine, rt, 12 h–48 h (50–97% yield); (c) Et₃N 3HF, THF, rt, 4 h (76–99% yield).

Scheme 3.. Synthesis of 13a–13e^a

^aReagents and conditions: (a) TBSOTf, pyridine, rt, 1 h (69% yield) (b) K₂CO₃, MeOH, rt (82% yield) (c) corresponding acid, EDCI, DMAP, DCM, rt (48–71% yields) (d) Py•HF, pyridine, rt, over two days (40–74% yield) (e) benzoic acid, EDCI, DMAP, DCM, rt, over 7 days/Dess-Martin periodinane, DCM, rt, overnight (48 and 80% yield) (f) Py•HF, pyridine, rt, over two days (80–94% yield).

Scheme 4.. Synthesis of 18 and 19a–19h^a

^aReagents and conditions (a) TBDMSCl, DMAP, pyridine, rt, 36 h (74% yield) (b) acetic anhydride, DMAP, pyridine, rt, 4h (58% yield) (c) Py•HF, pyridine, rt, over two days (45% yield) (d) acetic anhydride/benzoic anhydride/succinic anhydride/2,2-dimethylsuccinic anhydride, pyridine, DMAP,12 h–72 h; (e) Et₃N, DCM, (1S)-camphanic chloride/trans-4-methoxycinnamoyl chloride, rt, 12 h (24–53% yield).