Purine and Purine Isostere Derivatives of Ferrocene: An Evaluation of ADME, Antitumor and Electrochemical Properties.

Novel purine and purine isosteres containing a ferrocene motif and 4,1-disubstituted (11a-11c, 12a-12c, 13a-13c, 14a-14c, 15a-15c, 16a, 23a-23c, 24a-24c, 25a-25c) and 1,4-disubstituted (34a-34c and 35a-35c) 1,2,3-triazole rings were synthesized. The most potent cytotoxic effect on colorectal adenocarcinoma (SW620) was exerted by the 6-chloro-7-deazapurine 11c (IC50 = 9.07 µM), 6-chloropurine 13a (IC50 = 14.38 µM) and 15b (IC50 = 15.50 µM) ferrocenylalkyl derivatives. The N-9 isomer of 6-chloropurine 13a containing ferrocenylmethylene unit showed a favourable in vitro physicochemical and ADME properties including high solubility, moderate permeability and good metabolic stability in human liver microsomes.

Pharmacokinetic Evaluation of Brain Penetrating Morpholine-3-hydroxy-2-pyridine Oxime as an Antidote for Nerve Agent Poisoning.

Nerve agents, the deadliest chemical warfare agents, are potent inhibitors of acetylcholinesterase (AChE) and cause rapid cholinergic crisis with serious symptoms of poisoning. Oxime reactivators of AChE are used in medical practice in the treatment of nerve agent poisoning, but the search for novel improved reactivators with central activity is an ongoing pursuit. For numerous oximes synthesized, in vitro reactivation is a standard approach in biological evaluation with little attention given to the pharmacokinetic properties of the compounds. This study reports a comprehensive physicochemical, pharmacokinetic, and safety profiling of five lipophilic 3-hydroxy-2-pyridine aldoximes, which were recently shown to be potent AChE reactivators with a potential to be centrally active. The oxime JR595 was singled out as highly metabolically stable in human liver microsomes, noncytotoxic oxime for SH-SY5Y neuroblastoma and 1321N1 astrocytoma cell lines, and its pharmacokinetic profile was determined after intramuscular administration in mice. JR595 was rapidly absorbed into blood after 15 min with simultaneous distribution to the brain at up to about 40% of its blood concentration; however, it was eliminated from both the brain and blood within an hour. In addition, the MDCKII-MDR1 cell line assay showed that oxime JR595 was not a P-glycoprotein efflux pump substrate. Finally, the preliminary antidotal study against multiple LD50 doses of VX and sarin in mice showed the potential of JR595 to provide desirable therapeutic outcomes with future improvements in its circulation time.

Study of lipophilicity and membrane partition of 4-hydroxycoumarins by HPLC and PCA.

Physicochemical properties provide reliable guidance in optimization of pharmacological efficiency and ADME profile of small chemical compounds. Their high-throughput determination is regularly based on application of HPLC techniques. In this study CHI and CHI IAM of 32 4-hydroxycoumarin analogs were measured by HPLC with methanol gradient at pHs 2.8 and 7.0. Results were analyzed by PCA in terms of computed descriptors in order to identify space for optimization of their phospholipids affinity and lipophilicity for which predictive software failed to produce reliable estimations. The chromatographic behavior of studied 4-hydroxycoumarins was typical of acidic compounds. The CHI(2.8), CHI(7.0), CHI IAM(2.8) and CHI IAM(7.0) values were all considerably cross-correlated in accordance with their prevailing lipophilic character. Structure-retention relationship (SRR) analysis furthermore revealed that H-bond accepting capacity and dipolar interactions with methanol generally shorten their retention times. However, deviations from the linear trends were noticed for R3/R5-substituted derivatives able to form intramolecular contacts with the 4-O(H) group and characterized by more uniform electron density at 2-O and 4-O atoms and quite different acidity/H-bond donating capacity than the rest of derivatives. Thus, CHI and CHI IAM determinations and SRR analysis are fast and efficiently pointed to ways of modifying biological activities of 4-hydroxycoumarins.

Physicochemical profile of macrolides and their comparison with small molecules.

Macrolides are stereospecific macrolactones of high molecular weights. Herein, 600 mostly semisynthetic macrolides are compared with 50,000 small non-macrolide synthetic molecules in terms of measured physicochemical properties in order to assess the drug-likeness and developability chances of macrolides. The pre-selected set of diverse macrolides is comprised mostly of derivatives of clarithromycin and azithromycin cores. Lipophilicity (CHI logD), affinity for immobilized artificial membranes (CHI IAM), human serum albumin (HSA) and α(1)-acid glycoprotein (AGP) plasma protein bindings (PPB), DMSO precipitative solubility as well as artificial membrane permeability (AMP) have been determined by high-throughput screening methods. It has been found that macrolides and small molecules have similar lipophilicity profiles, though macrolides show weaker PPB and have better solubility than small discovery molecules. However, macrolides are poorly permeable and have high affinity for immobilized artificial membranes signifying their strong interaction with biological phospholipids. In order to retain the drug-like profile, the design of novel macrolide molecules should be focused on optimisation of macrolide cores, that is macrolactone moiety with sugars and other small substituents avoiding large substituents and flexible linkers such as in conjugate derivatives.

Determination of aqueous stability and degradation products of series of coumarin dimers.

The stability in aqueous solution of five classes of coumarin dimers (I-V, compounds 1-29) was studied by HPLC-MS/MS at various pH values. The relationship between chemical structure and stability is discussed. It was found that dimeric compounds with strong electron withdrawing groups (EWGs) on the α-carbon to the bridging C-atom are stable at all pH values, whereas other derivatives undergo retro-Michael addition at rates which are also affected by the substituents on the aromatic rings. In some cases formation of stable isomers or oxidation products was observed. In order to evaluate their developability and potential for progression to in vivo studies, representative compounds were tested in an in vitro microsomal stability assay.

ESI-MS studies of palladium (II) complexes with 1-(p-toluenesulfonyl)cytosine/cytosinato ligands.

The mononuclear complex Pd(1-TosC-N3)(2)Cl(2) (2) containing 1-(p-toluenesulfonyl)cytosine (1) as a ligand, as well as dinuclear complexes Pd(2)(1-TosC(-)-N3,N4)(4) (3) and Pd(2)(1-TosC(-)-N3,N4)(2)DMSO(2)Cl(2) (4) containing the ligand anion (1-TosC(-)), was mass analyzed by electrospray ionization ion trap MS/MS and high resolution MS. Complexes 3 and 4 were obtained by recrystallization of 2 from DMF and DMSO, respectively. The behavior of complex 2 in different solutions was monitored by electrospray ionization mass spectrometry (ESI-MS). Under the applied ESI-MS conditions, complex 2 in methanol reorganized itself dominantly as new complex 3 and the solvent did not coordinate the formed species. In H(2)O/DMSO, CH(3)CN/DMSO and CH(3)OH/DMSO solutions, complex 2 formed several new species with solvent molecules involved in their structure, e.g. complex 4 was formed as the major product. The newly formed species were also examined by LC-MS-DAD, confirming the solvent induced reorganization and the solution instability of complex 2.