Discovery of berberine analogs as potent and highly selective p300/CBP HAT inhibitors.

The protein p300 is a positive regulator of cancer progression and is related to many human pathological conditions. To find effective p300/CBP HAT inhibitors, we screened an internal compound library and identified berberine as a lead compound. Next, we designed, synthesized, and screened a series of novel berberine analogs, and discovered that analog 5d was a potent and highly selective p300/CBP HAT inhibitor with IC50 values of 0.070 µM and 1.755 µM for p300 and CBP, respectively. Western blotting further proved that 5d specifically decreased H3K18Ac and interfere with the function of histone acetyltransferase. Although 5d had only a moderate inhibitory effect on the MDA-MB-231 cell line, 5d suppressed the growth of 4T1 tumor growth in mice with a tumor weight inhibition ratio (TWI) of 39.7%. Further, liposomes-encapsulated 5d increased its inhibition of tumor growth to 57.8 % TWI. In addition, 5d has no obvious toxicity to the main organ of mice and the pharmacokinetic study confirmed that 5d has good absorption properties in vivo.

Synthesis and antitumor activity of a series of novel N-aryl-5-(2,2,2-trifluoroethoxy)-1,5-dihydro-2H-pyrrol-2-ones derivatives.

With the help of the establishment of novel reaction methodology, a series of N-Aryl-5-(2,2,2-trifluoroethoxy)-1,5-dihydro-2H-pyrrol-2-one conjugates were designed and synthesized in 2-4 steps, and subsequent anticancer activity of these compounds was evaluated. Preliminary results showed that these compounds have moderate to potent activities against human acute leukemia cells K562, human lung cancer A549, human breast cancer MDA-MB-231, and human cervical cancer HeLa cancer cell lines. Among them, compounds 2d and 2k were the most potent against K562 cell line with IC50 values of 0.07 and 0.52 µM, respectively, and the toxicity of 2d to the normal of hepatocytes (LO2) cell line was low (the survival rate 81 %). Flow cytometry analysis showed that 2d arrested K562 cells in the G2/M phase potently, even much better than Combretastatin A4 (CA4). In addition, the results demonstrated the involvement of the caspase-dependent or independent pathways of apoptosis, evidenced by the upregulation of FADD, pro-caspase 3, cleaved-caspase 3, HTRA2/Omi, SMAC/Diablo and the ratio of Bax/Bcl-2.The biological effects founding of 2d in this work point to prospective uses against acute leukemia.

Design, synthesis, and antitumor study of a series of novel 1-Oxa-4-azaspironenone derivatives.

A series of 1-oxa-4-azaspiro[4,5]deca-6,9-diene-3,8-dione derivatives containing structural fragments of conjugated dienone have been synthesized previously by our group, however the Michael addition reaction between conjugated dienone and nucleophilic groups in the body may generate harmful and adverse effects. To reduce harmful side effects, the authors started with p-aminophenol to make 1-oxo-4- azaspirodecanedione derivatives, then utilized the Michael addition and cyclopropanation to eliminate α, ß unsaturated olefinic bond and lower the Michael reactivity of the compounds in vivo for optimization. At the same time, heteroatoms are put into the molecules in order to improve the hydrophilicity of the molecules and the binding sites of the molecules and the target molecules, establishing the groundwork for improved antitumor activity. The majority of the compounds had moderate to potent activity against A549 human lung cancer cells, MDA-MB-231 breast cancer cells, and Hela human cervical cancer cells. Among them, the compound 6d showed the strongest effect on A549 cell line with IC50 of 0.26 µM; the compound 8d showed the strongest cytotoxicity on MDA-MB-231 cell line with IC50 of 0.10 µM; and the compound 6b showed the strongest activity on Hela cell line with IC50 of 0.18 µM.

Design, synthesis, and evaluation of a novel series of mono-indolylbenzoquinones derivatives for the potential treatment of breast cancer.

Breast cancer is one of the most common cancers in the world, and pro-apototic drugs activating the apoptotic pathway are a strategy for anticancer therapy. To explore new antineoplastic agents, a series of novel mono-indolylbenzoquinone derivatives have been designed and synthesized. Compared with the lead bis-indolylbenzoquinones, most of the novel mono-indolylbenzoquinone derivatives have significantly increased their activity against A549, HeLa, and especially, MDA-MB-231 cell lines. Among them, 10d has the lowest IC50 value of 70 nM on MDA-MB-231 cells. Moreover, its oral toxicity is extremely low with an LD50 value of 374 mg/kg and no obvious liver and kidney damage to mice. 10d down-regulated Bcl-2, up-regulated Bax, and increased the release of cytochrome C, caspase3 and 9. 10d also up-regulated the expression of p53, catalase, and HTRA2/Omi. Therefore, 10d may exert its anticancer activity by activating apoptotic pathway and p53 expression. In vivo, 10d suppressed breast cancer 4T1 tumor growth with 36% inhibition ratio of tumor by intraperitoneal injection in mice. Furthermore, a cross-linked cyanoacrylate (CA)-based local sustained-release drug delivery systems (LSRDDSs) improved 10d anticancer activity to 49.8% inhibition of tumor growth. Taken together, 10d could be a promising drug candidate for clinical development to treat metastatic breast cancer.

Design, synthesis, and antitumor activity evaluation of novel acyl sulfonamide spirodienones.

Based on the promising results of benzenesulfonamide spirodienones as antineoplastic agents, we have designed and synthesized a series of novel acyl sulfonamides spirodienone for antineoplastic evaluation. Of these, compound 4a exhibited remarkable in vitro antiproliferative activity by arresting the cell cycle and inducing apoptosis of MDA-MB-231 cells. Acute toxicity study has demonstrated 4a at 100 mg/kg dose caused no obvious toxicity to the major organs of mice. Moreover, compound 4a suppressed the growth of murine 4T1 tumor in vivo. Preliminary enzyme assay showed that 4a was a potential MMP2 inhibitor for cancer therapy. In all, these results indicate that compound 4a may be a lead compound for the development of anticancer agents.