Recent Progress in the Development of HIV-1 Entry Inhibitors: From Small Molecules to Potent Anti-HIV Agents.

Viral entry, the first process in the reproduction of viruses, primarily involves attachment of the viral envelope proteins to membranes of the host cell. The crucial components that play an important role in viral entry include viral surface glycoprotein gp120, viral transmembrane glycoprotein gp41, host cell glycoprotein (CD4), and host cell chemokine receptors (CCR5 and CXCR4). Inhibition of the multiple molecular interactions of these components can restrain viruses, such as HIV-1, from fusion with the host cell, blocking them from reproducing. This review article specifically focuses on the recent progress in the development of small-molecule HIV-1 entry inhibitors and incorporates important aspects of their structural modification that lead to the discovery of new molecular scaffolds with more potency.

Scale-Up Synthesis and In Vivo Anti-Tumor Activity of Curcumin Diethyl Disuccinate, an Ester Prodrug of Curcumin, in HepG2-Xenograft Mice.

Previously, we synthesized curcumin and a succinate ester prodrug of curcumin namely curcumin diethyl disuccinate (CurDD) in the lab scale, which yielded hundred milligrams to few grams of the compounds. CurDD was found to be more stable in a phosphate buffer pH 7.4 and exhibited better cytotoxicity against Caco-2 cells than curcumin. Here, the one-pot syntheses of curcumin and CurDD were scaled up to afford multigram quantities of both compounds for preclinical studies using a 10-L chemical reactor. The key steps for the synthesis of curcumin were the formation of boron-acetylacetone complex and the decomplexation of boron-curcumin complex. The synthesis of CurDD could be achieved via a one-step esterification between curcumin and succinic acid monoethyl ester chloride using 4-(N,N-dimethylamino)pyridine as a catalyst. The synthesized curcumin and CurDD were then investigated and compared for an anti-tumor activity in HepG2-xenograft mice. CurDD could reduce the tumor growth in HepG2-xenograft mice better than curcumin. CurDD also exerted the stronger inhibition on VEGF secretion, COX-2 and Bcl-2 expression and induced higher Bax expression in comparison with curcumin. The results suggest that CurDD is a promising prodrug of curcumin and has a potential to be further developed as a therapeutic agent or an adjuvant for the treatment of hepatocellular carcinoma.