Synthesis of Hydantoin Androgen Receptor Antagonists and Study on Their Antagonistic Activity.

Hydroxymethylthiohydantoin, hydroxymethylthiohydantoin, and hydantoin, containing a pyridine group, were synthesized to study their androgen receptor antagonistic activities. Among them, compounds 6a/6c/7g/19a/19b exhibited excellent androgen receptor antagonistic activity, which was consistent with or even superior to enzalutamide. In addition, compounds 19a and 19b exhibited better antiproliferative activity than enzalutamide in prostate cancer cells. The results show that compound 19a has great potential as a new AR antagonist.

Chiral Brønsted acid catalyzed asymmetric oxidation of N-acyl sulfenamide by H2 O2 : An efficient approach to obtaining chiral N-acyl sulfinamide.

Although the power of chiral sulfinamide reagents in synthetic chemistry has long been recognized, methods for their synthesis are still auxiliary-based approaches which possess the disadvantages of poor atom economy and limited substrate universality. Due to the weak nucleophilicity of amides, it is more difficult to prepare chiral N-acylsulfinamides by traditional methods. Herein, we describe an example of catalytic asymmetric synthesis of N-acyl sulfinamides. In this work, N-acyl sulfenamides act as useful substrates, because of the indispensable N-H bond, which could form an efficient hydrogen bond with chiral phosphoric acid. H2 O2 (35%) was used as the terminal oxidant for preparation of sulfinamides in high yields and enantioselectivities, which could be easily derivatized to sulfoxides without loss of the enantioselectivity.

Plumbagin exhibits an anti-proliferative effect in human osteosarcoma cells by downregulating FHL2 and interfering with Wnt/ß-catenin signalling.

Plumbagin, a naphthoquinone constituent of Plumbago zeylanica L. (Plumbaginaceae) is widely used in traditional Chinese medicine as an antifungal, antibacterial and anti-inflammatory agent. Plumbagin is known to exhibit proapoptotic, antiangiogenic and antimetastatic effects in cancer cells. The transcriptional co-factor four and a half LIM domains 2 (FHL2) is a multifunctional adaptor protein that is involved in the regulation of gene expression, signal transduction and cell proliferation and differentiation, and also acts as a tumor suppressor or oncoprotein depending on the tissue microenvironment. The present study investigated the effect of plumbagin on FHL2 expression, Wnt/ß-catenin signalling and its anti-proliferative activity in various human osteosarcoma cell lines, including SaOS2, MG63, HOS and U2OS. The cells were exposed to plumbagin and the expression of FHL2 was evaluated using western blot analysis. Furthermore, the anti-proliferative effect of plumbagin was evaluated using a 3-(4,5 dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. In addition, since FHL2 is involved in Wnt/ß-catenin signaling, the effect of plumbagin on ß-catenin and its primary target genes, including v-myc avian myelocytomatosis viral oncogene homolog (c-Myc) and WNT1 inducible signaling pathway protein-1 (WISP-1), was evaluated using western blot analysis. It was observed that plumbagin suppressed the expression of FHL2 and exhibited significant anti-proliferative activity in osteosarcoma cells. It also attenuated Wnt/ß-catenin signalling by downregulating ß-catenin and its target genes, including c-Myc and WISP-1. In conclusion, plumbagin demonstrated anti-proliferative activity in osteosarcoma cells by downregulating FHL2 and interfering with Wnt/ß-catenin signalling.

10-Boronic acid substituted camptothecin as prodrug of SN-38.

Malignant tumor cells have been found to have high levels of reactive oxygen species such as hydrogen peroxide (H2O2), supporting the hypothesis that a prodrug could be activated by intracellular H2O2 and lead to a potential antitumor therapy. In this study, the 7-ethyl-10-boronic acid camptothecin (B1) was synthesized for the first time as prodrug of SN-38, by linking a cleavable aryl carbon-boron bond to the SN-38. Prodrug B1 selectively activated by H2O2, converted rapidly to the active form SN-38 under favorable oxidative conditions in cancer cells with elevated levels of H2O2. The cell survival assay showed that prodrug B1 was equally or more effective in inhibiting the growth of six different cancer cells, as compared to SN-38. Unexpectedly, prodrug B1 displayed even more potent Topo I inhibitory activity than SN-38, suggesting that it was not only a prodrug of SN-38 but also a typical Topo I inhibitor. Prodrug B1 also demonstrated a significant antitumor activity at 2.0 mg/kg in a xenograft model using human brain star glioblastoma cell lines U87MG.

Design, synthesis and biological evaluation of novel homocamptothecin analogues as potent antitumor agents.

Fifteen novel homocamptothecin derivatives with α-OMe substituted E-rings were designed and synthesized. All of the derivatives exhibited similar or superior cytotoxicities compared with that of SN-38, and they inhibited Topo I activity in a cell-free assay in a manner similar to that of SN-38, confirming that they represent a new class of Topo I inhibitors. Notably, the water soluble compound 36o (1.2 mg/mL) exhibited increased lactone stability, and at 0.5 mg/kg and 3.0 mg/kg, it demonstrated significant antitumor activity in mice bearing a xenograft model using human colon cancer cell line HT-29. On the basis of these positive results, further development of 36o-related compounds as potential anticancer clinical trial candidates is definitely warranted.