Tricarbonyl rhenium(i) complexes with 8-hydroxyquinolines: structural, chemical, antibacterial, and anticancer characteristics.

Twelve tricarbonyl rhenium(i) complexes in the '2 + 1' system with the anionic bidentate N,O-donor ligand (deprotonated 8-hydroxyquinoline (HQ) or its 2-methyl (MeHQ) or 5-chloro (ClHQ) derivative) and neutral N-donor diazoles (imidazole (Him), 2-methylimidazole (MeHim), 3,5-dimethylpyrazole (Hdmpz), and 3-phenylpyrazole (HPhpz)) were synthesized: [Re(CO)3(LN,O)LN] (LN,O = Q-, MeQ-, ClQ-; LN = Him, MeHim, Hdmpz, HPhpz). Their crystal structures were determined by the scXRD method, compared with the DFT-calculated ones, and characterized by analytical (EA) and spectroscopic techniques (FT-IR, NMR, and UV-Vis) interpreted with DFT and TD-DFT calculations. Most of the Re(i) complexes did not show relevant antibacterial activity against Gram-negative and Gram-positive bacterial strains. Only [Re(CO)3(MeQ)Him] demonstrated significant action 4-fold better against Gram-negative Pseudomonas aeruginosa than the free MeHQ ligand. The cytotoxicity of the compounds was estimated using human acute promyelocytic leukemia (HL-60), ovarian (SKOV-3), prostate (PC-3), and breast (MCF-7) cancer, and breast non-cancerous (MCF-10A) cell lines. Only HQ and ClHQ ligands and [Re(CO)3(Q)Hdmpz] complex had good selectivity toward MCF-7 cell line. HL-60 cells were sensitive to all complexes (IC50 = 1.5-14 µM). Still, pure HQ and ClHQ ligands were slightly more active than the complexes.

Preliminary study of mechanism of action of SN38 derivatives. Physicochemical data, evidence of interaction and alkylation of DNA octamer d(GCGATCGC)2.

The synthesis of water-soluble SN38 derivatives is presented, and their stability in solutions used during drug development studies has been investigated. A preliminary study of mechanism of action of 9-aminomethyl SN38 is presented. Using NMR techniques, the interaction of the oligomer d(GCGATCGC)2 is studied, showing that the terminal GC base pairs are the main site of interaction. Using pulsed field gradient spin echo and mass spectroscopy, evidence of a spontaneous alkylation reaction of the DNA oligomer with SN38 derivatives is presented. A proposed mechanism of reaction is suggested. Copyright © 2016 John Wiley & Sons, Ltd.

Molecular docking studies, biological and toxicity evaluation of dihydroisoquinoline derivatives as potential anticancer agents.

We report a study of a series of isoquinoline derivatives, including their synthesis, in vitro microsomal leucine aminopeptidase (LAP) inhibition and antiproliferative activity on cancer cell lines. Among fourteen tested compounds, one (compound 3b) was determined to have good activity against LAP and significant antiproliferative activity against HL-60 human promyelocytic leukemia, Burkitt's lymphoma Raji, camptothecin resistant CEM/C2 leukemia cells with mutated catalytic site of topoisomerase I, its parental cell line CCRF/CEM and LoVo colon cancer. Its influence on the cell cycle was also observed. Moreover, we have confirmed that antiproliferative activity towards cancer cells is due to LAP inhibition. Docking simulation based on positioning compound 3b into the LAP active site was performed to explore the possible binding mode. The compound was able to form hydrogen bonds with Gly362 and coordinate zinc ions, which was previously suggested to be essential for inhibitory activity. Compound 3b was also characterized with a good selectivity index for cancer versus normal mammalian cells. Toxicological studies involving examination of skin sensitization, acute skin irritation/corrosion, acute dermal toxicity, acute oral toxicity and acute eye irritation/corrosion established that compound 3b is safe for use.

Genistein binding mode to doubly nicked dumbbell DNA. Dynamic and diffusion ordered NMR study.

New genistein derivatives were synthesized, which are fairly well soluble in water, with respect to parent genistein, and thus facilitate study of the interaction with dumbbell DNA dodecamer, mimicking the biological target for topoisomerase II inhibitors. A pulsed field gradient spin echo NMR experiment was used to check the binding and to estimate the association constants and its pH dependence of genistein with dumbbell DNA. Experimental restraints based on nuclear Overhauser spectroscopy spectra were used to calculate the NMR structure in solution in case of 6,8-disubstituted genistein with dimethylaminomethyl groups and were used in molecular modeling calculations. The structure is dynamic, and 10 molecular dynamics runs yield a family of conformations that essentially differ in a depth of inclusion of genistein into a nick. The paper experimentally shows evidence for binding, intercalation in the nick is proposed as a mode of genistein binding, and a model of the event is provided.

Topotecan dynamics, tautomerism and reactivity--1H/13C NMR and ESI MS study.

Topotecan (TPT) is in clinical use as an antitumor agent, hycamtin. Because of this, it requires both biologically and chemically useful information to be available. TPT acts by binding to the covalent complex formed by nicked DNA and topoisomerase I. This has a poisonous effect since inserted into the single-strand nick and TPT inhibits its religation. We used NMR to trace TPT dynamics, tautomerism and solvolysis products in various solvents and conditions. Chemical stability was assessed in methanol and DMSO as compared to water, and the regioselectivity of the N- and O-methylation was studied using various alkylating agents. The reaction products of quaternization of the nitrogen atom and methylation of the oxygen atom were characterized by means of ESI MS, (1)H/(13)C-HMBC and -HSQCAD NMR. We have focused on the NMR characterization of TPT with an anticipation that its aggregation, tumbling properties and the intramolecular dipolar interactions will be a common feature for other compounds described in this article. These features can also be useful in tracing the interactions of this class of topoisomerase I (TopoI) poisons with DNA. Moreover, the results explained shed light on the recently disclosed problem of lack of stability of TPT in the heart tissue homogenate samples using the analytical assays developed for this class of compounds carried out in the presence of methanol.

Structure and dynamics of methyl cis-3,4-diamino-2,3,4,6-tetradeoxy-alpha-L-lyxo-hexopyranoside complexes with PtCl(2) and PdCl(2), by (1)H, (2)H, (13)C, (15)N and (195)Pt NMR spectroscopy in DMSO, CD(3)CN and H(2)O.

Pd(II) and Pt(II) chloride complexes with LL = methyl cis-3,4-diamino-2,3,4,6-tetradeoxy-alpha-l-lyxo-hexopyranoside of the formulae [Pd(LL)Cl(2)] and [Pt(LL)Cl(2)], 1, were studied by (1)H, (2)H, (13)C, (15)N and (195)Pt NMR spectroscopy. These techniques were applied for characterization of the structure and ligand exchange dynamics, in case of diastereomeric species formed from 1 in DMSO-d(6), DMSO-h(6) and H(2)O; their general formula was [Pt(LL)XY](+) (X = Cl, Y = DMSO-d(6), 2a; X = DMSO-d(6), Y = Cl, 2b; X = Cl, Y = DMSO-h(6), 2a'; X = DMSO-h(6), Y = Cl, 2b'; X = Cl, Y = H(2)O, 3a; X = H(2)O, Y = Cl, 3b). Their theoretical structures and NMR parameters, calculated at the level of DFT approach, were also presented and compared to the experimental data. The model complex [Pt(trans-diaminocyclohexane)Cl(2)], 4, was studied as well. To the best of our knowledge, this work is the first account dealing with the detailed analysis of structure and dynamics of ligand exchange processes in organic solvents and water, performed for a PtCl(2) complex containing a diaminosugar moiety. The kinetic behavior of the studied coordination compounds suggests that some of them may be potentially active in bioassays against cancer cells. Compound 1 exhibits noticeable versatile ligand exchange possibilities in DMSO and H(2)O. Particularly, it undergoes solvolysis in DMSO-d(6), exchanging one chloride atom and yielding two diastereomers 2a and 2b; the former, being the kinetically favored species, has the DMSO-d(6) ligand syn to the N(3) atom. The lyophilisate of the respective 2a + 2b mixture, earlier equilibrated in DMSO-d(6), after dissolving in H(2)O yields only the latter isomer, which is thermodynamically favored. The solvolysis of 1 in H(2)O yields instantaneously two diastereomeric monoaquated species, 3a and 3b, amounting to 10% of each.