Design, synthesis and biological evaluation of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates containing sulfonamido as potential PI3Kα inhibitors.

A series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates contained sulfonamido were designed and synthesized, and their anticancer effects in vitro was evaluated to develop some new PI3Kα inhibitors. Most of desired compounds exhibited the better antiproliferative activities against four cancer cell lines than that of LY294002. Out of them, compound 4o displayed the potent antiproliferative activity and high selectivity against the PI3Kα protein and it can induce apoptosis of HCT116 in a dose-dependent manner. Western blot assay indicated that compound 4o obviously down-regulated expression of p-Akt (S473). Molecular docking was performed to clarify the possible binding mode between compound 4o and PI3Kα. All these results indicated that compound 4o could be a potential inhibitor of PI3Kα.

Development of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates containing piperazine as inhibitors of PI3Kα.

PI3K pathway has been heavily studied and is one of the most potential targets for various cancer treatment. Herein, we designed and synthesized a series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates contained piperazine based on our previous research. They were evaluated for their PI3Kα wild-type and H1047R mutant inhibitory activities and anticancer effects in vitro. Most of these compounds displayed the potential antiproliferative activities against four cancer cell lines (HCT-116, A549, Huh7 and HL60). Among them, Compound 4p revealed the remarkable antiproliferative activity and was selected for further biological evaluation. Compound 4p displayed the potent activity against both PI3Kα wild-type and H1047R mutant, and a certain degree of selectivity for PI3Kα over PI3Kß, γ and δ, and meanwhile it can remarkable down-regulate the phosphorylation of Akt. In addition, compound 4p was found to induce cell apoptosis via upregulation of Bax and cleaved-caspase 3/9, and downregulation of Bcl-2. The above results suggested that compound 4p could be considered as a promising PI3Kα inhibitor.

9a-Hy-droxy-3,8a-dimethyl-5-methyl-ene-4,4a,5,6,9,9a-hexa-hydro-naphtho-[2,3-b]furan-2(8aH)-one.

The title compound, C(15)H(18)O(3), was isolated from Lacta-rius piperatus (Fr.) S. F. Gary collected from the Kunming area in Yunnan province, China. The central cyclo-hexyl ring adopts a chair conformation, while the furan-one ring is close to planar (r.m.s. deviation = 0.0174 Å). The remaining methyl-ene cyclo-hexene ring has a flattened chair conformation. In the crystal, mol-ecules are linked via inter-molecular O-H⋯O and C-H⋯O hydrogen bonds into zigzag chains along the a axis.

2-Meth-oxy-naphthalene-1,4-dione.

The title compound, C(11)H(8)O(3), was isolated from Impatiens balsamina plants (balsam, LIB) grown in our laboratory. The two six-membered rings of the naphthalene-1,4-dione unit are coplanar [maximum deviation = 0.009 (1) Å]. The O and C atoms of the meth-oxy substituent also lie close to the naphthalene plane, with deviations of 0.0090 (2) and 0.047 (2) Å, respectively.

(E)-4-Chloro-N-(2,4,6-trimethyl-benzyl-idene)aniline.

In the title compound, C(16)H(16)ClN, the dihedral angle between the benzene rings is 24.61 (13)°. In the crystal, only van der Waals inter-actions occur between neighbouring mol-ecules.

3-(tert-But-oxy-carbon-yl)-2-(4-chloro-phen-yl)-1,3-thia-zolidine-4-carb-oxy-lic acid.

In the title compound, C(15)H(18)ClNO(4)S, the thia-zolidine ring adopts a twisted conformation about the S-C(methyl-ene) bond. The dihedral angle between the five- and six-membered rings is 77.2 (3)°. In the crystal, the mol-ecules are linked by O-H⋯O hydrogen bonds, generating C(7) chains propagating in [100].

(2R,4R)-3-(tert-But-oxy-carbon-yl)-2-(3-chloro-phen-yl)-1,3-thia-zolidine-4-carb-oxy-lic acid monohydrate.

In the title compound, C(15)H(18)ClNO(4)S·H(2)O, the thia-zolidine ring displays a half-chair conformation. In the crystal, the water mol-ecules are linked to the organic acid mol-ecules via inter-molecular O-H⋯O hydrogen bonds.

Development of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates bearing sulfonylpiperazine as antitumor inhibitors targeting PI3Kα.

PI3K signal pathway plays a vital role in cellular functions and becomes an attractive approach for cancer therapy. Herein, a new series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivatives bearing sulfonylpiperazine based on the PI3K inhibitors and our previous research. They were screened for their PI3K inhibitory activities and anticancer effects in vitro. Biological studies indicated that compound 7m revealed the remarkable antiproliferative activity (IC50 ranging from 0.03 to 0.09 µM) against four cancer cell lines (A549, Huh7, HL60 and HCT-116). Besides, compound 7m displayed a certain selective for PI3Kα (IC50 = 0.009 µM) over PI3Kß, γ and δ, and meanwhile, it can remarkable decreased the expression level of p-Akt (Ser473) and p-S6K. In addition, compound 7m could not only induce HCT-116 cell arrest at G1 phase in a dose-dependent manner, but also induce cell apoptosis via upregulation of Bax and cleaved-caspase 3/9, and downregulation of Bcl-2. Besides, compound 7m can remarkably inhibit the growth of tumor in vivo. The above results suggested that compound 7m could be considered as a promising PI3Kα inhibitor.

Targeted antimicrobial moieties (WO2010080819): patent evaluation.

The verification of refined variants of already existing medicines proved to be a breakthrough for antibiotic research. However, resistance to old and newer antibiotics among microbacillary pathogens is evolving quickly. Drug-resistant pathogens have become an important economic burden for patients. This invention (WO2010080819) provides novel targeting moieties (peptides) that specifically/preferentially bind to microorganisms. The targeting moieties can be attached to effectors to form chimeric constructs for specifically/preferentially delivering the effector to and/or into the target organism. In certain embodiments, novel antimicrobial peptides that can be used to inhibit of certain microorganisms are provided.

Synthesis, structure and structure-activity relationship analysis of 3-tert-butoxycarbonyl-2-arylthiazolidine-4-carboxylic acid derivatives as potential antibacterial agents.

Nine 2-arylthiazolidine-4-carboxylic acid derivatives and nine 3-tert-butoxycarbonyl-2-arylthiazolidine-4-carboxylic acid derivatives were synthesized to screen for their antibacterial activities. Compounds 5, 14-18 were first reported. Their chemical structures were clearly determined by (1)H NMR, (13)C NMR, ESI mass spectra and elemental analyses, coupled with one selected single-crystal structure. All the compounds were assayed for antibacterial activities against two Gram-positive bacterial strains (Bacillus subtilis ATCC 6633 and Staphylococcus aureus ATCC 6538) and two Gram-negative bacterial strains (Escherichia coli ATCC 35218 and Pseudomonas aeruginosa ATCC 13525) by MTT method. Most of the 3-tert-butoxycarbonyl-2-arylthiazolidine-4-carboxylic acid derivatives exhibited better antibacterial activities against the four bacterial strains than relative 2-arylthiazolidine-4-carboxylic acid derivatives. Compound (2RS,4R)-3-(tert-butoxycarbonyl)-2-(5-fluoro-2-hydroxyphenyl)thiazolidine-4-carboxylic acid (14) showed powerful antibacterial activities against P. aeruginosa with IC(50) value of 0.195 microg/mL, which was superior to the positive controls Penicillin G and Kanamycin B, respectively. On the basis of the biological results, structure-activity relationships were discussed.

Synthesis, antiproliferative activity, and structure-activity relationships of 3-aryl-1H-quinolin-4-ones.

The antiproliferative activities of 36 3-aryl-1H-quinolin-4-ones were determined against two cancer cell lines (Hep G2 and KB) in vitro. The results indicate that most of these compounds show good cytotoxic activity against human cancer cell lines, but no cytotoxicity against a human normal cell line (L02). The positive control compounds genistein and 5-fluorouracil show no selectivity at inhibiting the growth of the above three cell lines. Generally, compounds that bear a halogen atom at the 8 position and a methoxy group at the 3' position exhibited remarkable cytotoxicity toward human cancer cell lines. Electron-withdrawing substituents at the 6 position decrease the antiproliferative activity significantly. We also put forward a pharmacophore model for 3-aryl-4-quinolinones binding with epidermal growth factor receptor protein tyrosine kinases (EGFR PTK). Out of the 36 synthetic compounds, 34 are reported for the first time.

[Mechanical property analysis of polyethylene fiber reinforced polymethyl methacylate].

OBJECTIVE: To investigate if the Ribbond polyethylene fiber has the effect of reinforcing polymethyl methacylate. METHODS: 28 specimens were fabricated and divided into 3 groups: group of chemical-cured PMMA, group of chemical-cured PMMA reinforced by stainless steel wire and group of chemical-cured PMMA reinforced by Ribbond polyethylene fiber. A three-point bending test was used to measure the flexural strength and flexural modulus of specimens. Then the data were analyzed with a one-way analysis of variance. RESULTS: The flexural strength of chemical-cured PMMA group was (51.383 +/- 2.761) MPa, the flexural modulus was (1791.2 +/- 113.760) MPa; The flexural strength of stainless steel wire reinforced group was (58.725 +/- 1.218) MPa, the flexural modulus was (2092.76 +/- 120.28) MPa; The flexural strength of Ribbond polyethylene fiber reinforced group was (80.975 +/- 2.58) MPa, the flexural modulus was (2866.53 +/- 107.51) MPa. The one-way analysis of variance showed that the results were significant (P < 0.001). Newman-Keuls method showed that the differences among all groups were significant (P < 0.05). CONCLUSION: The Ribbond polyethylene fiber can raise the flexural strength and flexural modulu of polymethyl methacylate.