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Download fileSynthesis and Structure–Activity Relationship Correlations of Gnidimacrin Derivatives as Potent HIV‑1 Inhibitors and HIV Latency Reversing Agents
journal contribution
posted on 25.07.2019, 20:14 authored by Qingbo Liu, Yung-Yi Cheng, Wei Li, Li Huang, Yoshihisa Asada, Min-Tsang Hsieh, Susan L. Morris-Natschke, Chin-Ho Chen, Kazuo Koike, Kuo-Hsiung LeeCurrently, 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.