On the basis of structures of known topoisomerase II catalytic inhibitors and initial molecular docking studies, bicyclic N-fused aminoimidazoles were predicted as potential topoisomerase II inhibitors. They were synthesized by multicomponent reactions and evaluated against human topoisomerase IIα (hTopoIIα) in decatenation, relaxation, cleavage complex, and DNA intercalation in vitro assays. Among 31 compounds of eight different bicyclic scaffolds, it was found that imidazopyridine, imidazopyrazole, and imidazopyrazine with suitable substituents exhibited potent inhibition of catalytic activity of hTopoIIα while not showing DNA intercalation. Molecular docking studies and molecular dynamics (MD) simulation analysis, ATPase-kinetics and ATP-dependent plasmid relaxation assay revealed the catalytic mode of inhibition of the title compounds plausibly by blocking the ATP-binding site. N-Fused aminoimidazoles showed potent anticancer activities in kidney and breast cancer cell lines, low toxicity to normal cells, relatively higher potency compared to etoposide and 5-fluorouracil in kidney cancer cell lines, and potent inhibition in cell migration. These compounds were found to exert apoptotic effect in G1/S phase.
Combretastatin A-4 (CA-4) in phosphate and serine pro-drug forms is under phase II clinical trials. With our interest of discovering CA-4 inspired new chemical entities, a novel series of 4,5-diaryl-2-aminoimidazole analogues of the compound was designed and synthesized by an efficient and diversity feasible route involving atom economical arene C-H bond arylation. Interestingly, four compounds showed potent cell-based antiproliferative activities in nanomolar concentrations. Among the compounds, compound 12 inhibited the proliferation of several types of cancer cells much more efficiently than CA-4. It depolymerized microtubules, induced spindle defects, and stalled mitosis in cells. Compound 12 bound to tubulin and inhibited the polymerization of tubulin in vitro. In addition, podophyllotoxin and CA-4 inhibited the binding of compound 12 to tubulin. The distinctive pharmacophoric features of the bridging motif as well as quinoline nucleus were explored. We noted also a valuable quality of compound 12 as a potential probe in characterizing new CA-4 analogues.
An efficient method for regio- and chemoselective Friedel-Crafts acylation of indole using acyl chlorides in the presence of ZrCl(4) has been discovered. It minimizes/eliminates common competing reactions that occur due to high and multiatom-nucleophilic character of indole. In this method, a wide range of aroyl, heteroaroyl alkenoyl, and alkanoyl chlorides undergo smooth acylation with various indoles without NH protection and afford 3-acylindoles in good to high yields.
The catalytic efficiency of mixed Cu(I)-Cu(II) system in situ generated by partial reduction of CuSO(4) with glucose in ethanol (nonanhydrous) under open air has been explored. With this catalysis, the multicomponent cascade reaction of A(3)-coupling of heterocyclic amidine with aldehyde and alkyne, 5-exo-dig cycloisomerization, and prototropic shift has afforded an efficient and eco-friendly synthesis of therapeutically important versatile N-fused imidazoles. Diverse heterocyclic amidines, several of which are known to be poorly reactive, and aldehydes are compatible in this catalytic process.
A novel microwave-promoted protocol mediated by Mn(OAc) 3 was developed for the single-electron-transfer oxidative direct C-H bond arylation of (hetero)arenes with aryl and heteroarylboronic acids. Various electron-deactivated and electron-rich heteroarenes and benzene underwent successfully the direct arylation in this general process. The use of slight excess of heteroarene or benzene in this method was found to be sufficient.
An oxidative dearomatization chemistry of 2-arylindole via a unique pathway involving Pd-catalyzed C-H peroxygenation is documented. Coupled with cascade transformation, it provides a new route to access indolin-3-ones bearing a C2-quaternary functionality, including a chiral center (indoxyls), a motif prevalent in indole alkaloids but synthetically underexplored. The method is chemo- and regioselective and compatible with versatile substrates. A mechanism has been outlined on the basis of results of control experiments, isolation/use of intermediates, and spectroscopic studies.
An Ugi-type multicomponent reaction of heterocyclic amidines with aldehydes and isocyanides catalyzed by zirconium(IV) chloride in PEG-400 was developed. The protocol offers the rapid, environment friendly, regioselective and versatile synthesis of medicinally important N-fused 2-and 3-aminoimidazoles in good to high yields. The combination of catalyst and solvent, that was judiciously explored, was crucial for regioselectivity and versatility of the method.
Combretastatin
(CA-4) and its analogues are undergoing several
clinical trials for treating different types of tumors. In this work,
the antiproliferative activity of a series of 2-aminoimidazole-carbonyl
analogs of clinically relevant combretastatins A-4 (CA-4) and A-1
was evaluated using a cell-based assay. Among the compounds tested,
C-13
and
C-21
displayed strong antiproliferative
activities against HeLa cells.
C-13
inhibited the proliferation
of lung carcinoma (A549) cells more potently than combretastatin A-4.
C-13
also retarded the migration of A549 cells. Interestingly,
C-13
displayed much stronger antiproliferative effects against
breast carcinoma and skin melanoma cells compared to noncancerous
breast epithelial and skin fibroblast cells.
C-13
strongly
disassembled cellular microtubules, perturbed the localization of
EB1 protein, inhibited mitosis in cultured cells, and bound to tubulin
at the colchicine site and inhibited the polymerization of reconstituted
microtubules in vitro.
C-13
treatment increased the level
of reactive oxygen species and induced apoptosis via poly(ADP-ribose)
polymerase-cleavage in HeLa cells. The results revealed the importance
of the 2-aminoimidazole-carbonyl motif as a double bond replacement
in combretastatin and indicated a pharmacodynamically interesting
pattern of H-bond acceptors/donors and requisite syn-templated aryls.
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