Mingfeng Zhang

Design and synthesis of cyclopropylamide analogues of combretastatin-A4 as novel microtubule-stabilizing agents.

A series of novel cyclopropylamide analogues of combretastatin-A4 (CA-4) were designed and synthesized. Most of them had significant in vitro antiproliferative activities, particularly for compounds 7i4, 7c4, 8a4, and 8c4. Moreover, compound 8c4 was also equally potent against paclitaxel resistant cancer cells. Interestingly, the novel cyclopropylamide analogues had different binding mechanisms from CA-4. Instead of inhibiting tubulin polymerization, these CA-4 derivatives were able to stimulate tubulin polymerization. Flow cytometry revealed that compound 8c4 arrested A549 cancer cells in the G2/M phase and resulted in cellular apoptosis. Further immunofluorescence assays revealed that compound 8c4 induced mitotic arrest in A549 cells through disrupting microtubule dynamics. In addition, compound 8c4 also effectively inhibited the tumor growth in the A549 xenograft model without causing significant loss of body weight. Compound 8c4 represents a novel class of microtubule-stabilizing agent and can be used as a promising lead for the development of new antitumor agents.

Convenient synthesis of novel geiparvarin analogs with potential anti-cancer activity via click chemistry.

Based on the advantages of natural products in new anti-cancer drug development, we synthesized a series of novel benzopyran-4-one derivatives and evaluated their in vitro anti-cancer activities. The bioassays showed that the majority of the resultant compounds exerted anti-tumor effect against six human cancer cell lines to various extents, which supported the rationale of the design. Compound 5s exhibited highest potency of all the synthesized compounds.

Synthesis and anti-tumor activity of novel ethyl 3-aryl-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-carboxylates.

A series of ethyl 3-aryl-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-carboxylates were prepared through the metal-catalyzed domino reaction of alkylidene malonates and 1,4-butynediol under a one-pot reaction condition at room temperature. Their in vitro anti-proliferative activities were subsequently evaluated in A549, QGY and HeLa cells. The majority of the compounds showed potent anti-tumor activity against HeLa cells. In particular, compound 3l was the most potent compound with IC(50) value of 5.4 μM. For the first time, the X-ray structure of the anti-tumor ethyl 3-aryl-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-carboxylates is determined.

Anti-hepatitis B virus and anti-cancer activities of novel isoflavone analogs.

We have synthesized a series of novel isoflavone analogs and evaluated their anti-HBV and anti-cancer activities in vitro. The bioassays showed that the majority of the resultant compounds exerted inhibitory effects on HBsAg and HBeAg levels, HBV DNA replication, as well as the growth of four human cancer cell lines to various extents, which supported the rationale of the design. In particular, compound 8f showed the highest activity against HBV infection and HBV-related liver cancer. Compound 7l (IC50 = 0.47 μM) also exerted remarkable inhibitory effect on the growth lung cancer cell line A-549.

Synthesis and in vitro antifungal activities of new 3-substituted benzopyrone derivatives

A series of new benzopyrone compounds were designed and synthesized and their antifungal activities in vitro were evaluated. The results showed that the benzopyrone derivatives with short terminal alkyl chain exhibited potent antifungal activity, which represent a novel class of promising leads for the development of novel non-azole antifungal agents. Compound 5j is the most potent one with MIC(80) value 1.5 μg/mL against Trichophyton rubrum. Flexible molecular docking was used to analyze the structure-activity relationships (SARs) of the compounds. The designed compounds interact with CA-CYP51 through hydrophobic and van der Waals interactions.