K. Mantelingu

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. The link of the overexpression and tumorigenesis is yet to be understood. By employing virtual screening, we have found that anacardic acid, a pentadecane aliphatic chain containing hydroxylcarboxylic acid, from cashew nut shell liquid could be docked in Aurora kinases A and B. Remarkably, we found that anacardic acid could potently activate the Aurora kinase A mediated phosphorylation of histone H3, but at a similar concentration the activity of aurora kinase B remained unaffected in vitro. Mechanistically, anacardic acid induces the structural changes and also the autophosphorylation of the aurora kinase A to enhance the enzyme activity. This data thus indicate anacardic acid as the first small-molecule activator of Aurora kinase, which could be highly useful for probing the function of hyperactive (overexpressed) Aurora kinase A.

Diastereoselective synthesis of fused oxazolidines and highly substituted 1H-pyrrolo [2,1-c][1,4] oxazines via C–H functionalization

The first one pot protocol for the diastereoselective synthesis of oxazolo[2,3-c]isoquinoline was achieved by a metal-free, benzoic acid catalyzed reaction of 1,2,3,4-tetrahydroisoquinoline or trypoline with aldehydes under mild conditions via C–H, C–O bond functionalization. A new approach for the synthesis of highly substituted 1H-pyrrolo[2,1-c][1,4]oxazine was carried out.

Highly diastereoselective synthesis of polycyclic amines via redox neutral C–H functionalization

Synthesis of polycyclic amines was achieved by benzoic acid catalysed reaction of 1-aryl THIQs and 1-aryl trypolines with o-allyl salicylaldehydes through the in situ generated azomethine ylide intermediates that undergo intramolecular [3+2]-cycloadditions with four new stereogenic centers in excellent diastereoselectivities under simple and mild conditions.

Recyclable, Graphite-Catalyzed, Four-Component Synthesis of Functionalized Pyrroles

Abstract A facile, convenient, and multicomponent coupling strategy for the synthesis of highly functionalized pyrroles is developed using graphite as a catalyst, but devoid of moisture-sensitive metal catalysts and corrosive acidic reagents. This method involves four-component coupling reactions of ethyl acetoacetate compound or diethyl acetylene dicarboxylate, amines, aromatic aldehydes, and nitromethane without an inert atmosphere. This approach provides easy access to highly substituted pyrroles in good yields via one-pot tandem reaction. The method is very simple, straightforward, and environmentally friendly compared to the existing methods. [Supplementary materials are available for this article. Go to the publishers online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.] GRAPHICAL ABSTRACT

TRIFLUOROETHANOL AS A METAL-FREE, HOMOGENEOUS, AND RECYCLABLE MEDIUM FOR THE EFFICIENT ONE-POT SYNTHESIS OF DIHYDROPYRIMIDONES

Abstract Trifluoroethanol is an efficient and recyclable medium in promoting one-pot, three-component condensation reactions of β-ketoesters, aldehydes, and urea (or thiourea) to afford the corresponding dihydropyrimidones in good yields. This protocol does not require the use of an acid or base catalyst. GRAPHICAL ABSTRACT

An unexpected reaction to methodology: an unprecedented approach to transamidation

This report describes an unprecedented protocol for the synthesis of N,N′-substituted ureas using a cross-coupling method. Mono substituted ureas were modified by an economically viable and simple method using commercially available isocyanates and sodium hydride as the reagents. In addition, the method involves no expensive metal complexes or catalysts and all reactions are carried out at room temperature. Furthermore, both symmetrical and asymmetrical ureas were successfully obtained in single step reactions with reasonable yields.

Synthesis and Antiproliferative efficiency of novel bis(imidazol-1-yl)vinyl-1,2,4-oxadiazoles

A new approach for the synthesis of novel bis(imidazol-1-yl)vinyl-1,2,4-oxadiazoles has been developed. This method operates in a single step giving the products in good to excellent yields. Antiproliferative efficiency of the synthesized compounds was tested against HCT116 (colon cancer) and A549 (lung cancer) cell lines. Among them, compounds 3m (IC50, 9.7 μM) and 3h (IC50, 20.3 μM) were found to be the best antiproliferative agents.

Novel and Efficient Method for the Synthesis of Racemic Fexofenadine

Abstract Fexofenadine is a selective H1-histamine receptor antagonist, which is an attractive alternative treatment for allergy symptoms. An efficient and environmentally friendly synthetic approach for the preparation of fexofenadine was developed from commercially available cumene. The method involves the Friedel–Crafts reaction, substitution, reduction, bromination, and the Grignard reaction.

Novel PARP inhibitors sensitize human leukemic cells in an endogenous PARP activity dependent manner

Poly(ADP-ribose) polymerase (PARP) is a critical nuclear enzyme which safeguards genome stability from genotoxic insults and helps in DNA repair. Inhibition of PARP results in sustained DNA damage in cancer cells. PARP inhibitors are known to play an important role in chemotherapy as single agents in many DNA repair pathway deficient tumor cells or in combination with several other chemotherapeutic agents. In the present study, we synthesize and characterize novel pyridazine derivatives, and evaluate their potential for use as PARP inhibitors. Results show that pyridazine derivatives inhibited the PARP1 enzymatic activity at the nanomolar range and showed anti-proliferative activity in leukemic cells. Interestingly, human leukemic cell line, Nalm6, in which PARP1 and PARP2 expression as well as intrinsic PARP activity are high, showed significant sensitivity for the novel inhibitors compared to other leukemic cells. Among the inhibitors, P10 showed maximum inhibition of intrinsic PARP activity and inhibited cell proliferation in Nalm6 cells. Besides P10 also showed maximum inhibition against purified PARP1 protein, which was comparable to olaparib in our assays. Newly synthesized compounds also showed remarkable DNA trapping ability, which is a signature feature of many PARP inhibitors. Importantly, P10 also induced late S and G2/M arrest in Nalm6 cells, indicating accumulation of DNA damage. Therefore, we identify P10 as a potential PARP inhibitor, which can be developed as a chemotherapeutic agent.

Synthesis and biological evaluation of tetrahydropyridinepyrazoles (‘PFPs’) as inhibitors of STAT3 phosphorylation

The transcription factor STAT3 is constitutively overexpressed in many human tumors and hence represents a putative target for anticancer drug design. In this work, we describe the synthesis and biological evaluation of a novel chemotype, pyridine-fused pyrazoles (‘PFPs’) as inhibitors of STAT3 phosphorylation. The effect of the compounds synthesized was evaluated in cell proliferation assays of MCF-7 and HepG2 cancer cell lines and two of the compounds tested (12g and 12k) were found to show significant activity. Both compounds were also found to inhibit the proliferation of Hep3B, HUH-7 and PLC/PRF5 HCC cells in a dose- and time-dependent manner. Furthermore, we established in a DNA binding assay that one of the compounds (12g) was able to significantly inhibit the DNA binding ability of STAT3. Cytotoxicity of 12g against PC3 cells, which do not constitutively phosphorylate STAT3, was found to be minimal, hence lending further support for our mode-of-action hypothesis of this compound. We established for this structure a complete inhibition of CXCL12-induced cell invasion and associated wound healing in HCCLM3 cells, corroborating the proposed modulation of the STAT3 axis by 12g. Finally, molecular modeling was employed to evaluate the hypothesis of PFPs to bind to the SH2 domain of STAT3. Given the efficacy of PFPs in the biological systems studied here we propose their further evaluation in the context of STAT3-mediated cancer therapy.