Novel Synthetic Indazoles Abrogate Angiogenesis in Erlich Ascites Tumor Bearing Mice.

Background: Indazoles are known for their anti-cancer properties.

Objective: The current investigation was on the synthesis and evaluation of novel indazole derivatives for their anticancer properties.

Methods: A series of novel indazoles were synthesized and characterized by IR, NMR and LCMS.

A panoramic view on synthetic applications of α-oxothioamides: a highly regioselective synthesis of 2-acyl-4-(het)arylthiazoles and thioethers.

Highly regioselective synthesis of 2-acyl-4-(het)arylthiazoles and thioethers by the reaction between α-oxothioamides and α-bromoketones in the absence of base in DMF and in the presence of triethylamine in acetonitrile, respectively, has been reported. This thiazole synthesis is an important extended work of the Hantzsch thiazole synthesis, which overcomes the drawbacks of earlier reported methods. The probable mechanisms for the formation of thiazoles and thioethers are also presented.

Identification and characterization of mercaptopyrimidine-based small molecules as inhibitors of nonhomologous DNA end joining.

Mercaptopyrimidine derivatives are heterocyclic compounds with potent biological activities including antiproliferative, antibacterial, and anti-inflammatory properties. The present study describes the synthesis and characterization of several mercaptopyrimidine derivatives through condensation of 5,6-diamino-2-mercaptopyrimidin-4-ol with various heterocyclic and aromatic aldehydes. Previous studies have shown that SCR7, synthesized from 5,6-diamino-2-mercaptopyrimidin-4-ol, induced cytotoxicity by targeting cancer cells by primarily inhibiting DNA Ligase IV involved in nonhomologous end joining, one of the major DNA double-strand break repair pathways.

Co(CO) as a Solid CO (g) Source for the Amino Carbonylation of (Hetero)aryl Halides with Highly Deactivated (Hetero)arylamines.

Carbonylation of (hetero)aryl iodides/bromides with highly deactivated 2-aminopyridines using Pd-Co(CO) bimetallic catalysis is accomplished. The use of Co(CO) as a solid CO(g) source enhanced reaction rates observed when compared to CO(g), and excellent yields highlight the versatility of the developed protocol. A wide range of electronically and sterically demanding heterocyclic amines and (hetero)aryl iodides/bromides employed for this study resulted in excellent yields of amino carbonylated products.

Acute toxicity analysis of Disarib, an inhibitor of BCL2.

Small molecule inhibitors targeting BCL2 are explored as anticancer therapeutics. Previously, we have reported identification and characterization of a novel BCL2 inhibitor, Disarib. Disarib induced cancer cell death in a BCL2 dependent manner in different cancer cell lines and mouse tumor models when it was administered intraperitoneally.

I-Catalyzed transformation of o-aminobenzamide to o-ureidobenzonitrile using isothiocyanates.

The present work describes an unexpected and unique protocol for the iodine catalysed synthesis of o-ureidobenzonitriles using o-aminobenzamides and isothiocyanates via intramolecular rearrangement. The metal-free route achieved here is insensitive to moisture and applicable to the synthesis of a wide variety of o-ureidobenzonitriles with excellent yields even in a scalable fashion.

Identification and characterization of novel SCR7-based small-molecule inhibitor of DNA end-joining, SCR130 and its relevance in cancer therapeutics.

Targeting DNA repair with small-molecule inhibitors is an attractive strategy for cancer therapy. Majority of DNA double-strand breaks in mammalian cells are repaired through nonhomologous end-joining (NHEJ). It has been shown that small-molecule inhibitors of NHEJ can block efficient repair inside cancer cells, leading to cell death.

Crystal structures of three 6-aryl-2-(4-chloro-benz-yl)-5-[(1-indol-3-yl)meth-yl]imidazo[2,1-][1,3,4]thia-diazo-les.

Three title compounds, namely, 2-(4-chloro-benz-yl)-5-[(1-indol-3-yl)meth-yl]-6-phenyl-imidazo[2,1-][1,3,4]thia-diazole, CHClNS, (I), 2-(4-chloro-benz-yl)-6-(4-fluoro-phen-yl)-5-[(1-indol-3-yl)meth-yl]imidazo[2,1-][1,3,4]thia-diazole, CHClFNS, (II), and 6-(4-bromo-phen-yl)-2-(4-chloro-benz-yl)-5-[(1-indol-3-yl)meth-yl]imidazo[2,1-][1,3,4]thia-diazole, CHBrClNS, (III), have been prepared using a reductive condensation of indole with the corresponding 6-aryl-2-(4-chloro-benz-yl)imidazo[2,1-][1,3,4]thia-diazole-5-carbaldehydes (aryl = phenyl, 4-fluoro-phenyl or 4-bromo-phen-yl), and their crystal structures have been determined. The asymmetric unit of compound (I) consists of two independent mol-ecules and one of the mol-ecules exhibits disorder of the 4-chloro-benzyl substituent with occupancies 0.6289 (17) and 0.

Autocyclized and oxidized forms of SCR7 induce cancer cell death by inhibiting nonhomologous DNA end joining in a Ligase IV dependent manner.

Nonhomologous DNA end joining (NHEJ) is the major DNA double-strand break (DSB) repair pathway in mammals. Previously, we have described a small molecule inhibitor, SCR7, which can inhibit NHEJ in a Ligase IV-dependent manner. Administration of SCR7 within the cells resulted in the accumulation of DNA breaks, cell death, and inhibition of tumor growth in mice.

Combinatorial Study of a Novel Poly (ADP-ribose) Polymerase Inhibitor and an HDAC Inhibitor, SAHA, in Leukemic Cell Lines.

Background: Cancer is a multifactorial disease, which makes it difficult to cure. Since more than one defective cellular component is often involved during oncogenesis, combination therapy is gaining prominence in the field of cancer therapeutics.

Objective: The purpose of this study was to investigate the combinatorial effects of a novel PARP inhibitor, P10, and HDAC inhibitor, SAHA, in leukemic cells.

Intramolecular [3 + 2]-cycloadditions of azomethine ylides derived from secondary amines via redox-neutral C-H functionalization.

Azomethine ylides are accessed under mild conditions via benzoic acid catalyzed condensations of 1,2,3,4-tetrahydroisoquinolines or tryptolines with aldehydes bearing a pendent dipolarophile. These intermediates undergo intramolecular [3 + 2]-cycloadditions in a highly diastereoselective fashion to form polycyclic amines with four new stereogenic centers. Challenging substrates such as piperidine, morpholine, and thiomorpholine undergo the corresponding reactions at elevated temperatures.

Ethyl 1,4-bis-(4-chloro-phen-yl)-2-methyl-1H-pyrrole-3-carboxyl-ate.

In the title mol-ecule, C20H17Cl2NO2, the pyrrole moiety makes dihedral angles of 63.42 (11) and 70.43 (12)° with the chlorobenzene rings.

2-(1,3-Benzodioxol-5-yl)-3-phenyl-quinazolin-4(3H)-one.

In the mol-ecule of the title compound, C21H14N2O3, the quinazoline ring system [maximum deviation = 0.076 (1) Å] makes dihedral angles of 40.57 (9) and 42.

Differential effects of garcinol and curcumin on histone and p53 modifications in tumour cells.

Background: Post-translational modifications (PTMs) of histones and other proteins are perturbed in tumours. For example, reduced levels of acetylated H4K16 and trimethylated H4K20 are associated with high tumour grade and poor survival in breast cancer. Drug-like molecules that can reprogram selected histone PTMs in tumour cells are therefore of interest as potential cancer chemopreventive agents.

Nitric oxide-mediated histone hyperacetylation in oral cancer: target for a water-soluble HAT inhibitor, CTK7A.

Altered histone acetylation is associated with several diseases, including cancer. We report here that, unlike in most cancers, histones are found to be highly hyperacetylated in oral squamous cell carcinoma (OSCC; oral cancer) patient samples. Mechanistically, overexpression, as well as enhanced autoacetylation, of p300 induced by nucleophosmin (NPM1) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) causes the hyperacetylation, which is nitric oxide (NO) signal dependent.

Identification of a novel inhibitor of coactivator-associated arginine methyltransferase 1 (CARM1)-mediated methylation of histone H3 Arg-17.

Methylation of the arginine residues of histones by methyltransferases has important consequences for chromatin structure and gene regulation; however, the molecular mechanism(s) of methyltransferase regulation is still unclear, as is the biological significance of methylation at particular arginine residues. Here, we report a novel specific inhibitor of coactivator-associated arginine methyltransferase 1 (CARM1; also known as PRMT4) that selectively inhibits methylation at arginine 17 of histone H3 (H3R17). Remarkably, this plant-derived inhibitor, called TBBD (ellagic acid), binds to the substrate (histone) preferentially at the signature motif, "KAPRK," where the proline residue (Pro-16) plays a critical role for interaction and subsequent enzyme inhibition.

Specific small-molecule activator of Aurora kinase A induces autophosphorylation in a cell-free system.

Aurora kinases are essential for chromosomal segregation and cell division and thereby important for maintaining the proper genomic integrity. There are three classes of aurora kinases in humans: A, B, and C. Aurora kinase A is frequently overexpressed in various cancers.

Specific inhibition of p300-HAT alters global gene expression and represses HIV replication.

Reversible acetylation of histone and nonhistone proteins plays pivotal role in cellular homeostasis. Dysfunction of histone acetyltransferases (HATs) leads to several diseases including cancer, neurodegenaration, asthma, diabetes, AIDS, and cardiac hypertrophy. We describe the synthesis and characterization of a set of p300-HAT-specific small-molecule inhibitors from a natural nonspecific HAT inhibitor, garcinol, which is highly toxic to cells.

Activation of p300 histone acetyltransferase by small molecules altering enzyme structure: probed by surface-enhanced Raman spectroscopy.

Reversible acetylation of nucleosomal histones and nonhistone proteins play pivotal roles in the regulation of all the DNA templated phenomenon. Dysfunction of the enzymes involved in the acetylation/deacetylation leads to several diseases. Therefore, these enzymes are the targets for new generation therapeutics.

Synthesis of new bioactive venlafaxine analogs: novel thiazolidin-4-ones as antimicrobials.

A one-pot, three-component, microwave irradiated and conventional solution-phase synthesis of bioactive venlafaxine analogs such as 2,3-disubstituted-1,3-thiazolidin-4-ones 3a-j under mild conditions and their characterization are reported. The novel thiazolidin-4-ones, 3-(2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl)-2-phenyl-thiazolidin-4-one 3a, 2-(2,6-difluorophenyl)-3-(2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl)thiazolidin-4-one 3c, and 2-(furan-2-yl)-3-(2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)ethyl)thiazolidin-4-one 3i, were characterized by the single crystal X-ray diffraction method. The cyclohexane ring of all the three molecules is in chair conformation.

Solution-phase synthesis of novel delta2-isoxazoline libraries via 1,3-dipolar cycloaddition and their antifungal properties.

The synthesis of novel imidazolyl substituted delta2-isoxazoline libraries are currently of high interest. We report here in the full details of a study leading to the synthesis and antifungal activities of 3-(-2-butyl-4-chloro-1H-imidazolyl)-substituted delta2-isoxazolines. The solution phase synthesis of the title compounds was accomplished via 1,3-dipolar cycloaddition of in situ generated nitryl oxides from aldoximes with mono substituted alkenes to obtain the compound libraries contain an imidazole functionality in addition to the isoxazoline rings.

Synthesis and characterization of adenosine adducts of arylamines.

The synthesis of adducts of arylamines with adenosine are reported.