Synthesis and biological evaluation of epothilone A dimeric compounds

The preparation and biological evaluation of a novel series of dimeric epothilone A derivatives (1-6) are described. Two types of diacyl spacers were introduced to establish the various dimeric epothilone A constructs. The effect of these compounds on tubulin polymerization and their cytotoxicity against four different cancer cell lines are reported. Several of the newly synthesized compounds inhibit endothelial cell differentiation and endothelial cell migration that are key steps of the angiogenic process.

Synthesis and SAR of C12-C13-oxazoline derivatives of epothilone A

The SAR of a series of new epothilone A derivatives with a 2-substituted-1,3-oxazoline moiety trans-fused to the C12-C13 bond of the deoxy macrocycle have been investigated with regard to tubulin polymerization induction and cancer cell growth inhibition. Significant differences in antiproliferative activity were observed between different analogs, depending on the nature of the substituent at the 2-position of the oxazoline ring. The most potent compounds showed comparable activity with the natural product epothilone A. Modeling studies provide a preliminary rationale for the observed SAR.

Discovery of novel CB2 receptor ligands by a pharmacophore-based virtual screening workflow

Cannabinoid receptor 2 (CB(2) receptor) ligands are potential candidates for the therapy of chronic pain, inflammatory disorders, atherosclerosis, and osteoporosis. We describe the development of pharmacophore models for CB(2) receptor ligands, as well as a pharmacophore-based virtual screening workflow, which resulted in 14 hits for experimental follow-up. Seven compounds were identified with K(i) values below 25 microM. The CB(2) receptor-selective pyridine tetrahydrocannabinol analogue 8 (K(i) = 1.78 microM) was identified as a CB(2) partial agonist. Acetamides 12 (K(i) = 1.35 microM) and 18 (K(i) = 2.1 microM) represent new scaffolds for CB(2) receptor-selective antagonists and inverse agonists, respectively. Overall, our pharmacophore-based workflow yielded three novel scaffolds for the chemical development of CB(2) receptor ligands.

Synthesis of NO-donor bisphosphonates and their in-vitro action on bone resorption

A new class of bisphosphonates containing nitrooxy NO-donor functions has been developed. The products proved to display affinity for hydroxyapatite. Injection of (99m)Tc-labeled derivatives 11 and 18 into male rats showed a preferential accumulation of the compounds in bone as compared to blood and muscles. The products were found to inhibit the differentiation of pre-osteoclasts to functional osteoclasts induced by receptor activator of NF-kappaB ligand (RANKL), through a prevalent NO-dependent mechanism.

Synthesis and antibacterial evaluation of ureides of Baylis-Hillman derivatives

The synthesis of several 1-(2-cyano-3-aryl-allyl)-3-aryl-urea(thiourea) constructed from the reaction between allyl amines generated from Baylis-Hillman acetates and substituted isocyanates and isothiocyanates has been described. Further their cyclization in the presence of a base led to the formation of 5-arylmethyl-4-imino-3-aryl-3,4-dihydro-1H-pyrimidin-2-ones. All compounds were tested for their antibacterial activity. Few of the compounds showed superior activity or were equipotent to the standard antibacterial agents.

Combinatorial synthesis and biological evaluation of isoxazole-based libraries as antithrombotic agents

The 3-substitutedphenyl-5-isoxazolecarboxaldehydes have been identified as activated aldehydes for the generation of isoxazole-based combinatorial libraries on solid phase through automation. Three highly functionalized isoxazole-based libraries comprising of 32, 96 and 45 compounds each have been synthesized in parallel format using Baylis Hillman reaction, Michael addition, reductive amination and alkylation reactions. With an objective of lead generation all the three libraries were evaluated for their antithrombin activity in vivo.

CP-MLR Directed QSAR Studies on the Antimycobacterial Activity of Functionalised Alkenols - Topological Descriptors in Modeling the Activity

The antimycobacterial activity of nitro/ acetamido alkenol derivatives and chloro/ amino alkenol derivatives has been analyzed through combinatorial protocol in multiple linear regression (CP-MLR) using different topological descriptors obtained from Dragon software. Among the topological descriptor classes considered in the study, the activity is correlated with simple topological descriptors (TOPO) and more complex 2D autocorrelation descriptors (2DAUTO). In model building the descriptors from other classes, that is, empirical, constitutional, molecular walk counts, modified Burden eigenvalues and Galvez topological charge indices have made secondary contribution in association with TOPO and / or 2DAUTO classes. The structure-activity correlations obtained with the TOPO descriptors suggest that less branched and saturated structural templates would be better for the activity. For both the series of compounds, in 2DAUTO the activity has been correlated to the descriptors having mass, volume and/ or polarizability as weighting component. In these two series of compounds, however, the regression coefficients of the descriptors have opposite arithmetic signs with respect to one another. Outwardly these two series of compounds appear very similar. But in terms of activity they belong to different segments of descriptor-activity profiles. This difference in the activity of these two series of compounds may be mainly due to the spacing difference between the C1 (also C6) substituents and rest of the functional groups in them.

C-3 Alkyl /Arylalkyl-2,3-dideoxy hex-2-enopyranosides as Antitubercular Agents: Synthesis, Biological Evaluation and QSAR Study

A series of C-3 alkyl and arylalky 2,3-dideoxy hex-2-enopyranoside derivatives were synthesized by Morita-Baylis-Hillman reaction using enulosides 4, 5 and 6 and various aliphatic and aromatic aldehydes. The compounds were evaluated in vitro for the complete inhibition of growth of Mycobacterium tuberculosis H37Rv. They exhibited moderate to good activity in the range of 25-1.56 µg/mL. Among these, 4d, 4h, 5c and 4hr showed activity at minimum inhibitory concentrations, 3.12, 6.25, 1.56 and 1.56µg/mL, respectively. These compounds were safe against cytotoxicity in VERO cell line and mouse macrophage cell line J 744A.1. A QSAR analysis by CP-MLR with alignment-free 3D-descriptors indicated the relevance of structure space comparable to the minimum energy conformation (from conformational analysis) of 5c to the activity. The study indicates that the compounds attaining conformational space 5c and reflecting some symmetry, minimum eccentricity and closely placed geometric and electronegativity centers therein are favorable for activity.

Design, synthesis and pharmacological characterization of analogs of 2-aminoethyl diphenylborinate (2-APB), a known store-operated calcium channel blocker, for inhibition of TRPV6-mediated calcium transport

2-Aminoethyl diphenylborinate (2-APB) is a known modulator of the IP3 receptor, the calcium ATPase SERCA, the calcium release-activated calcium channel Orai and TRP channels. More recently, it was shown that 2-APB is an efficient inhibitor of the epithelial calcium channel TRPV6 which is overexpressed in prostate cancer. We have conducted a structure-activity relationship study of 2-APB congeners to understand their inhibitory mode of action on TRPV6. Whereas modifying the aminoethyl moiety did not significantly change TRPV6 inhibition, substitution of the phenyl rings of 2-APB did. Our data show that the diaryl borinate moiety is required for biological activity and that the substitution pattern of the aryl rings can influence TRPV6 versus SOCE inhibition. We have also discovered that 2-APB is hydrolyzed and transesterified within minutes in solution.

Thiazolides, a Novel Class of Anti-Infective Drugs, Effective Against Viruses, Bacteria, Intracellular and Extracellular Protozoan Parasites and Proliferating Mammalian Cells

The thiazolide nitazoxanide (2-acetolyloxy-N-(5-nitro 2-thiazolyl) benzamide; NTZ) is composed of a nitrothiazole- ring and a salicylic acid moiety, which are linked together through an amide bond. NTZ exhibits a broad spectrum of activities against a wide range of helminths, protozoa, enteric bacteria, and viruses infecting animals and humans. Since the first synthesis of the drug, a number of derivatives of NTZ have been produced, which are collectively named thiazolides. These are modified versions of NTZ, which include the replacement of the nitro group with bromo-, chloro-, or other functional groups, and the differential positioning of methyl- and methoxy-groups on the salicylate ring. The presence of a nitro group seems to be the prerequisite for activities against anaerobic or microaerophilic parasites and bacteria. Intracellular parasites and viruses, however, are susceptible to non-nitro-thiazolides with equal or higher effectiveness. Moreover, nitro- and bromo-thiazolides are effective against proliferating mammalian cells. Biochemical and genetic approaches have allowed the identification of respective targets and the molecular basis of resistance formation. Collectively, these studies strongly suggest that NTZ and other thiazolides exhibit multiple mechanisms of action. In microaerophilic bacteria and parasites, the reduction of the nitro group into a toxic intermediate turns out to be the key factor. In proliferating mammalian cells, however, bromo- and nitro-thiazolides trigger apoptosis, which may also explain their activities against intracellular pathogens. The mode of action against helminths may be similar to mammalian cells but has still not been elucidated.

Influence of perylenediimide–pyrene supramolecular interactions on the stability of DNA-based hybrids: Importance of electrostatic complementarity

Aromatic pi–pi stacking interactions are ubiquitous in nature, medicinal chemistry and materials sciences. They play a crucial role in the stacking of nucleobases, thus stabilising the DNA double helix. The following paper describes a series of chimeric DNA–polycyclic aromatic hydrocarbon (PAH) hybrids. The PAH building blocks are electron-rich pyrene and electron-poor perylenediimide (PDI), and were incorporated into complementary DNA strands. The hybrids contain different numbers of pyrene–PDI interactions that were found to directly influence duplex stability. As the pyrene–PDI ratio approaches 1:1, the stability of the duplexes increases with an average value of 7.5 °C per pyrene–PDI supramolecular interaction indicating the importance of electrostatic complementarity for aromatic pi–pi stacking interactions.

Cytotoxic peptide conjugates of dinuclear arene ruthenium trithiolato complexes

In order to improve the water-solubility of dinuclear thiolato-bridged arene ruthenium complexes, a new series was synthesized by conjugating octaarginine, octalysine, and cyclo[Lys-Arg-Gly-Asp-D-Phe] using chloroacetyl thioether (ClAc) ligation, resulting in cytotoxic conjugates against A2780 human ovarian cancer cells (IC50 = 2–8 μM) and against the cisplatin resistant line A2780cisR (IC50 = 7–15 μM). These metal complexes represent, to the best of our knowledge, the most cytotoxic ruthenium bioconjugates reported so far.