crystal structure of tris bis pentamethylene urea trinitratolanthanum iii la no3 3 c5h10n 2co 3

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Camptothecin-psammaplin A hybrids as topoisomerase I and HDAC dual-action inhibitors

Recent studies have demonstrated enhanced anticancer effects of combination therapy consisting of camptothecin derivatives and HDAC inhibitors. To exploit this synergy in a single active compound, we designed new dual-acting multivalent molecules simultaneously targeting topoisomerase I and HDAC. In particular, a selected compound containing a camptothecin and the psammaplin A scaffold showed a broad spectrum of antiproliferative activity, with IC50values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability

Design, modeling, synthesis and biological activity evaluation of camptothecin linked platinum anticancer agents

The design, modeling, synthesis and biological activity evaluation of two hybrid agents formed by 7-oxyiminomethylcamptothecin derivatives and diaminedichloro-platinum (II) complex are reported. The compounds showed growth inhibitory activity against a panel of human tumor cell lines, including sublines resistant to topotecan and platinum compounds. The derivatives were active in all the tested cell lines, and compound 1b, the most active one, was able to overcome cisplatin resistance in the osteosarcoma U2OS/Pt cell line. Platinum-containing camptothecins produced platinum-DNA adducts and topoisomerase I-mediated DNA damage with cleavage pattern and persistence similar to SN38, the active principle of irinotecan. Compound 1b exhibited an appreciable antitumor activity in vivo against human H460 tumor xenograft, comparable to that of irinotecan at lower well-tolerated dose levels and superior to cisplatin. The results support the interpretation that the diaminedichloro-platinum (II) complex conjugated via an oxyiminomethyl linker at the 7-position of the camptothecin resulted in a new class of effective antitumor compounds

7-Azaindole-1-carboxamides as a new class of PARP-1 inhibitors

7-Azaindole-1-carboxamides were designed as a new class of PARP-1 inhibitors. The compounds displayed a variable pattern of target inhibition profile that, in part, paralleled the antiproliferative activity in cell lines characterized by homologous recombination defects. A selected compound (1l; ST7710AA1) showed significant in vitro target inhibition and capability to substantially bypass the multidrug resistance mediated by Pgp. In antitumor activity studies against the MX1 human breast carcinoma growth in nude mice, the compound exhibited an effect similar to that of Olaparib in terms of tumor volume inhibition when used at a lower dose than the reference compound. Treatment was well tolerated, as no deaths or significant weight losses were observed among the treated animals

Hybrid topoisomerase i and HDAC inhibitors as dual action anticancer agents

Recent studies have shown that HDAC inhibitors act synergistically with camptothecin derivatives in combination therapies. To exploit this synergy, new hybrid molecules targeting simultaneously topoisomerase I and HDAC were designed. In particular, a selected multivalent agent containing a camptothecin and a SAHA-like template showed a broad spectrum of antiproliferative activity, with IC50 values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability

Structural and conformational studies on two diasteromeric dihydroisoxazolyl cyclopropane derivatives

The molecular structures of 2-(3'-bromo-4',5'-dihydroisoxazol-5'-yl)-1-tert-butoxycarbonylaminocyclo propanecarboxylic acid (\ub1)-10a and 1-amino-2-(3'-hydroxy-4',5'-diydroisoxazol-5'-yl)cyclopropanecarboxylic acid (\ub1)-11b were determined by single crystal X-ray diffraction method. The geometrical features and the intermolecular interactions of the two diastereoisomers have been compared evidencing a different conformation of the dihydroisoxazole ring: in (\ub1)-10a is almost planar, while in (\ub1)-11 adopts an envelope shape. Intermolecular hydrogen bonds of OH...O and NH...O type in (\ub1)-10a determine the formation of a three-dimensional network, whereas in (\ub1)-11b polimeric chains due to NH...O interactions are obtained. These compounds are key intermediates of conformationally constrained glutamic acid homologues and the opposite stereochemistry of C(3) leads to different pharmacophoric distances, important for the ligand-receptor interaction. The results of the X-ray molecular structures have been complemented by theoretical calculations

Green tea catechins in chemoprevention of cancer: A molecular docking investigation into their interaction with glutathione S-transferase (GST P1-1)

The anti- and pro-oxidant effects of green tea catechins have been implicated in the alterations of cellular functions determining their chemoprotective and therapeutic potentials in toxicity and diseases. The glutathione S-transferases (GSTs; EC 2.5.1.18) family is a widely distributed phase-II detoxifying enzymes and the GST P1-1 isoenzyme has been shown to catalyze the conjugation of GSH with some alkylating anti-cancer agents, suggesting that over-expression of GST P1-1 would result in tumor cell resistance. Here we report the docking study of four green tea catechins and four alkylating anticancer drugs into the GST P1-1 model, as GSTs were found to be affected by tea catechins. The EGCG ligands exhibit higher docking potential with respect to the anticancer agents, with a ligand-receptor interaction pattern indicating an high conformational stability. Consequently, the competition mechanisms favourable for the green tea catechins could lead to enzyme(s) desensitisation with a reduction of the alkylating drugs metabolism. The results provide a useful theoretical contribution in understanding the biochemical mechanisms implicated in the chemotherapeutic use of green tea catechins in oxidative stress-related diseases

Tetramethylammonium chlorodiphenylthiocyanatoantimonate(III)

The crystal structure of the title compound, (C4H12N)-[Sb(C6H5) Cl-2(NCS)], contains two cations and two anions in the asymmetric unit. The Sb atom exhibits a distorted pseudo-trigonal -bipyramidal coordination, with the phenyl groups and the lone pair of electrons in equatorial positions and N-bonded thiocyanate and Cl- ligands in axial positions

Docking of 6-chloropyridazin-3-yl derivatives active on nicotinic acetylcholine receptors into molluscan Acetylcholine Binding Protein (AChBP)

The crystal structure of Acetylcholine Binding Protein (AChBP), homolog of the ligand binding domain of nAChR, has been used as model for computational investigations on the ligand-receptor interactions of derivatives of 6-chloropyridazine substituted at C3 with 3,8-diazabicyclo[3.2.1] octane, 2,5-diazabicyclo[2.2.1]heptane and with piperazine and homopiperazine, substituted or not at N4. The ligand-receptor complexes have been analyzed by docking techniques using the binding site of HEPES complexed with AChBP as template. The good relationship between the observed binding affinity and the calculated docking energy confirms that this model provides a good starting point for understanding the binding domain of neuronal nicotinic receptors. An analysis of the possible factors significant for the ligand recognition has evidenced, besides the cation-\u3c6 interaction, the distance between the chlorine atom of the pyridazinyl group and the carbonylic oxygen of Leu B112 as an important parameter in the modulation of the binding energy