Search

Abstract Merbarone is a derivative of thiobarbituric acid, possessing catalytic inhibitory potential against human topoisomerase IIα (hTopoIIα). Merbarone was reported to inhibit DNA cleavage by hTopoIIα. It is important to understand the molecular mechanism of hTopoIIα inhibition by merbarone, as these details guide the rational design of new ligands. In this work, a systematic pharmacoinformatics analysis has been reported to analyze the merbarone-hTopoIIα interactions and to identify merbarone analogs as potential hTopoIIα inhibitors. The reported crystal structure of hTopoIIα-DNA complex (PDB ID: 4FM9) is not suitable for analyzing the merbarone-binding domain, because it is a biological assembly of hTopoIIα in C-gate open conformation. Therefore, 3D structure of hTopoIIα-DNA complex suitable for molecular modeling analysis at merbarone binding site was first generated. Using this generated complex, molecular docking analysis and molecular dynamics simulations were performed to explore the effect of merbarone on hTopoIIα-DNA complex. The binding energy for the enol form of merbarone with hTopoIIα-DNA was estimated to be −51.28 kcal/mol. The explored binding site and identified molecular recognition interactions were in accordance with the previously reported interference in the DNA-cleavage by merbarone. Virtual screening was performed using drug likeness filters, toxicity filters and ADMET descriptor based filters followed by molecular docking (ZINC database). Sixteen compounds were identified as merbarone-functional analogs suitable for hTopoIIα inhibition. These identified molecules can be considered for further evaluation of their anti-hTopoIIα activity. Graphical abstract Image 1 Highlights • The enzyme human topoisomerase IIα (hTopoIIα) is an important anticancer drug target. • The unavailability of sufficient structural details for hTopoIIα makes it difficult to understand the structural basis of drug action. • Merbarone is a potent anti-hTopoIIα agent, for which the molecular mechanism of hTopoIIα inhibition are not explored in detail. • A systematic molecular modeling approach is adopted to delineate the possible reason for merbarone induced catalytic inhibition of hTopoIIα. • The extracted information was utilized for virtual screening to identify promising anti-hTopoIIα agents acting at merbarone-binding site. [ABSTRACT FROM AUTHOR]

A new approach for the synthesis of tetrasubstituted/functionalized NH-pyrroles from gem-diactivated acrylonitriles and TMSCN has been developed. The strategy utilizes the generation of vic-dinitrile via Michael addition and cyanide-mediated nitrile-to-nitrile cyclocondensation, which proceed in tandem guided by manifold roles of "CN". An extended application to the production of fused pyrrole has also been realized. [ABSTRACT FROM AUTHOR]

A unique reactivity of a nitrile-stabilized quaternary ammonium ylide as a masked C–C=N synthon in contrast to its usual sigmatropic rearrangement has been demonstrated. Its reaction with 2-aminopyridine-derived aldimine undergoes electronically-assisted nucleophilic additions and Hofmann elimination, and provides a new method to access fused pyrimidines. [ABSTRACT FROM AUTHOR]

A step-economical access to polysubstituted aminoimidazoles has been accomplished via alkene vicinal C-N bonds formation of 2-bromo-2-alkenones with guanidine avoiding its NH-protection/derivatization prerequisite for electronic modulation. The approach has excellent substrate scope, is amenable to diverse guanidine-containing substrates, and introduces distinctive substitutions/functionalities into aminoimidazole core. It is also applicable to preparation of fused-imidazoles. The reaction involves a tandem pathway of aza-Michael addition, SN2, and a unique redox-neutral process, as evident by spectroscopic study and control experiments. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

A regioselective Ag(I)-promoted Pd-catalyzed C3-H activation-arylation of pyrido[1,2-a]pyrimidin-4-ones with bromo/iodo-(hetero)arenes under aqueous conditions has been developed. It affords an efficient access to pharmaceutically important versatile 3-aryl-pyrido[1,2-a]pyrimidin-4-ones. Interestingly, the arylation undergoes via a pathway with an unusual feature involving the formation of cationic arylpalladium species promoted by halo-sequestering Ag salts enabling concerted C3-palladation-deprotonation, as explored by relevant experiments and spectroscopic studies. The present approach is step economical, good yielding, and compatible with various functionalities and applicable to a wide range of starting materials. [ABSTRACT FROM AUTHOR]

A new and efficient approach for the synthesis of biologically important 2-aryl-4H-pyrido[1,2-a]pyrimidin-4-ones and 6-aryluracils via previously unknown Pd-catalyzed enolic C-OH activation-arylation of pyridopyrimidin-2,4-diones and barbituric acids, respectively, with boronic acids is reported. The starting materials are readily available, and products are obtained in high yields. An efficient and chemo- and stereoselective access to various tri- and tetrasubstituted conjugated alkenones and alkenoates is also obtained in this arylation approach. Interestingly, the procedure for the construction of such diverse molecular frameworks is general and featured with excellent substrates scope, tolerance of a broad range of functionalities, the unusual viability of performing the reaction under open air and in aqueous cosolvent, and the amenability to a scale-up synthesis, which have been found to be common limitations in the conventional/classical routes. The application of the protocol in a simple one-step high-yield route to pharmaceutically important polyarylated pyridopyrimidinone demonstrates its further synthetic utility. [ABSTRACT FROM AUTHOR]

A new reaction of aryl 2,3-epoxy esters with 2-aminopyridines has been developed that involves multiple C-O/C-N bond-breaking/formation reactions in one chemical step. Compared with known reactions of α,β-epoxy esters, which take place through oxiranyl C-O or C-C bond cleavage, the present reaction exploits the tendency of the oxirane ring to act as a bi-electrophile. Thus, the reaction follows a unique cascade pathway of epoxide C-O bond cleavage, formation of an α-enamine ester, and intramolecular transamidation with chemo-, regio- and diastereoselectivity. The reaction allows access to biologically relevant (Z)-2-methyleneimidazo[ 1,2-α]pyridin-3-ones. Water and ethanol are the only by-products. The reaction is flexible, and aryl 2,3-epoxy esters as well as 2-aminopyridines possessing either electron-donating or -withdrawing functionalities, can be used. In contrast to various Brønsted and Lewis acid catalysts, polyphosphoric acid plays a multifunctional role in this intermolecular cascade reaction. [ABSTRACT FROM AUTHOR]

Concerted metalation deprotonation (CMD) approach with appropriate proton shuttle precursor, base, and solvent (PivOH--K2CO3--toluene) has rendered a regioselective Pd-catalyzed C6-arylation of 3-aminoimidazo[1,2-a]pyrazine, a therapeutically relevant scaffold accessible by multicomponent reaction. The arylation of this heteroarene suffers from competing C5 and C2'-arylation reactions, while the developed process has virtually eliminated these competing arylanons. Density functional calculations for CMD C-H activation at C6, C5, C8, and C2' sites imply that the energy barrier with distortion energy penalty as major contributing component influences the regioselectivity. [ABSTRACT FROM AUTHOR]

Abstract: A Pd-catalyzed method has been developed for the intramolecular oxidative coupling of 3-indolylarylketones under open air as terminal oxidant toward the synthesis of indeno[1,2-b]indol-10(5H)-ones. This reaction represents an intramolecular coupling with dual activation of C–H bonds for electron-deficient arenes, while such reactions are common for electron-rich arenes. Pd(II)-catalysis with pivalic acid as co-catalyst has been found to be crucial. The reaction undergoes without indole N–H-protection. [Copyright &y& Elsevier]

The catalytic efficiency of mixed Cu(I)-Cu(II) system in situ generated by partial reduction of CuSO4 with glucose in ethanol (nonanhydrous) under open air has been explored. With this catalysis, the multicomponent cascade reaction of A³-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. [ABSTRACT FROM AUTHOR]

An efficient two-step approach, comprising the Friedel--Crafts reaction of 2-bromobenzoyl chlorides with indoles to give 3-(2-bromobenzoyl)indoles and their palladium-catalyzed intramolecular direct arylation to give indenoindolones, has been developed. 3-(2-Bromobenzoyl)indoles were crucial intermediates; the method was successful with N-unprotected or N-protected indoles. This approach affords a convenient preparation of diverse substituted and functionalized indenoindolones in good to high yields from easily accessible starting materials. Several moieties, which are commonly integrated into bioactive compounds, can be incorporated with ease by this synthesis. [ABSTRACT FROM AUTHOR]

An efficient two-step approach, comprising the Friedel- Crafts reaction of 2-bromobenzoyl chlorides with indoles to give 3- (2-bromobenzoyl)indoles and their palladium-catalyzed intramolecular direct arylation to give indenoindolones, has been developed. 3-(2-Bromobenzoyl)indoles were crucial intermediates; the method was successful with N-unprotected or N-protected indoles. This approach affords a convenient preparation of diverse substituted and functionalized indenoindolones in good to high yields from easily accessible starting materials. Several moieties, which are commonly integrated into bioactive compounds, can be incorporated with ease by this synthesis. [ABSTRACT FROM AUTHOR]

An efficient method for regio- and chemoselective Friedel-Crafts acylation of indole using acyl chlorides in the presence of ZrCl4 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. [ABSTRACT FROM AUTHOR]

Abstract: A new domino process of three-component Povarov reaction and aerobic dehydrogenation was developed toward the synthesis of polysubstituted quinolines. 2,4-Disubstituted-8-nitroquinolines, which are important precursors for the synthesis of antimalarial primaquine drug-like molecules, were prepared conveniently by this method in moderate to good yields. Brönsted acid (HClO4)-modified montmorillonite was found to be a crucial catalyst in promoting the procedure. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Abstract: We screened the National Cancer Institute Diversity Set compound collection for small molecules that affect mammalian cell migration and identified NSC 295642 as an inhibitor of cell motility with nanomolar potency. We found by LC–MS and X-ray crystallography that NSC 295642, a Cu(II) complex of the Schiff base product of condensation of S-benzyl dithiocarbazate and 2-acetylpyridine, has a bridged dimeric Cu2Cl2(L)2 structure with distorted square pyramidal geometry. Each of the two copper atoms is five-coordinated to one of the two tridentate chelating ligands and both bridging chlorine atoms. To define structure–activity relationships, we investigated the bioactivity of related metal–ligand complexes derived from different metal(II) atoms and different ligands. Complexation of the NSC 295642 ligand with Zn(II) or Ni(II), delivered as metal(II) chloride salts under conditions identical to those used for preparation of the original Cu(II) complex, instead results in distorted octahedral bis-chelate structures, where a single metal atom is six-coordinated to two ligands. The Zn(L)2 complex possesses a potency similar to that of the Cu2Cl2(L)2 complex, while the Ni(L)2 has no antimigratory activity at all. We carried out density functional theory calculations to obtain the electronic ground state geometry of the complexes, both in vacuum and implicit water solvent. The X-ray crystal and energy-minimized structures are very similar and exhibit a transoid orientation of the S-benzyl groups relative to the central metal-coordinated rings for both of the bioactive Cu2Cl2(L)2 and Zn(L)2 complexes, despite their different coordination geometries. In contrast, the biologically inactive Ni(L)2 complex adopts a cisoid conformation. Varying the ligand structure, we found that hydrophobic S-alkylaryl groups are required for activity. Complexes with a simple S-methyl group, S-benzyl groups with polar substitutions or a carboxylated pyridine ring exhibit dramatically reduced activity. We tested the most potent metal–ligand complex in a number of cancer cell lines and found cell-type selectivity in its effect on cell motility. Collectively, these results suggest that a two-ligand structure with bulky nonpolar S-substituents in a transoid conformation is important for the antimigratory activity of these metal–ligand complexes. [Copyright &y& Elsevier]

Abstract: A multicomponent method for scaffold-modification of nucleobases (adenine, guanine, and cytosine) was developed. This modification approach, as an alternative to usual synthetic routes involving protection–deprotection or SNAr of halo (or leaving group-equivalent)-purines, affords in one step therapeutically-relevant substituted aminoimidazole-[i]-condensed adenine, [b]-condensed guanine, [c]-condensed cytosine. These derived nucleobases possess enhanced lipophilicity and solubility and contain the functionalities useful for further chemical manipulations. [ABSTRACT FROM AUTHOR]

Palladium acetate catalyzed Mizoroki–Heck reactions of arylboronic acids with diethyl vinylphosphonates afford α,β-unsaturated phosphonates in good yields. [Copyright &y& Elsevier]

The reaction proceeds through a tandem sequence of desilylation followed by Strecker reaction, amide-forming cyclization and dehydrogenative aromatization. [ABSTRACT FROM AUTHOR]

An abstract of the article "Oxidative Dearomatization of Indoles via Pd-Catalyzed C-H Oxygenation: An Entry to C2-Quaternary Indolin-3-ones" is presented.

A direct regioselective C3-H arylation of pyrido[1,2-a]pyrimidin-4-ones using Pd(OAc)2 as the catalyst in the presence of Ag2CO3 as promotor is developed. [ABSTRACT FROM AUTHOR]

Palladium acetate catalyzed Mizoroki–Heck reaction of arylboronic acids with phenyl vinyl sulfones afford α,β-unsaturated sulfones in good yields. [Copyright &y& Elsevier]

An efficient Pd-catalyzed arylation process of enol-tosylates derived from 1,3-diones or barbituric acid with boronic acids is developed to allow the synthesis of the title compounds in generally good yields. [ABSTRACT FROM AUTHOR]

An abstract of the article "Desilylative Activation of TMSCN in Chemoselective Strecker-Ugi Type Reaction: Functional Fused Imidazoles as Building Blocks as an Entry Route to Annulated Purines" by S. K. Guchhait is presented.

Focuses on the chemoselective hydrogenation of phosphonates and alpha,beta-unsaturated sulfones through palladium-assisted hydrogen transfer in connection with the ammonium formate. How the reduction of phosphonates is usually carried out; Filtration of catalysts involved.

Pd(OAc)2/ PPh3/ PivOH-mediated treatment of 3-aminoimidazopyrazines with aryl bromides provides a new and regioselective approach to C6-arylated derivatives which are of biological interest. [ABSTRACT FROM AUTHOR]

The reaction does not require indole N-H protection. [ABSTRACT FROM AUTHOR]

The simple, efficient, and widely applicable method affords a broad spectrum of N-heterocyclic systems which are of therapeutic interest. [ABSTRACT FROM AUTHOR]

ZrCl4-mediated Friedel-Crafts acylation of indoles (I) with 2-bromobenzyl chlorides followed by Pd-catalyzed intramolecular C-2 arylation of the resulting 3-acylated indoles (III) offers a convenient synthesis of indenoindolones (IV). [ABSTRACT FROM AUTHOR]

[Display omitted] • Scaffold overlay of flavonoid-inspired bioactive molecules. • Dual hTopo-II and tubulin targeting anticancer agents. • Significant antiproliferative effects against various cancer cell line including drug-resistant cancer cells in nanomolar range. • The most active compound 5l showed remarkable inhibition of cancer cell migration, induced apoptosis in the G1/S phase transition of the cell cycle. • Cheminformatics analysis showed the compounds' favourable drug-relevant chemical space that is rarely represented by NPs. Almost half of all medicines approved by the U.S. Food and Drug Administration have been found to be developed based on inspiration from natural products (NPs). Here, we report a novel strategy of scaffold overlaying of scaffold-hopped analogs of bioactive flavones and isoflavones and installation of drug-privileged motifs, which has led to discovery of anticancer agents that surpass the functional efficiency of the original NPs. The analogs, 2,3-diaryl-pyridopyrimidin-4-imine/ones were efficiently synthesized by an approach of a nitrile-stabilized quaternary ammonium ylide as masked synthon and Pd-catalyzed activation–arylation methods. Compared to the NPs, these NP-analogs exhibited differentiated functions; dual inhibition of human topoisomerase-II (hTopo-II) enzyme and tubulin polymerization, and pronounced antiproliferative effect against various cancer cell lines, including numerous drug-resistant cancer cells. The most active compound 5l displayed significant inhibition of migration ability of cancer cells and blocked G1/S phase transition in cell cycle. Compound 5l caused pronounced effect in expression patterns of various key cell cycle regulatory proteins; up-regulation of apoptotic proteins, Bax, Caspase 3 and p53, and down-regulation of apoptosis-inhibiting proteins, BcL-xL, Cyclin D1, Cyclin E1 and NF-κB, which indicates high efficiency of the molecule 5l in apoptosis-signal axis interfering potential. Cheminformatics analysis revealed that 2,3-diaryl-pyridopyrimidin-4-imine/ones occupy a distinctive drug-relevant chemical space that is seldom represented by natural products and good physicochemical, ADMET and pharmacokinetic-relevant profile. Together, the anticancer potential of the investigated analogs was found to be much more efficient compared to the original natural products and two anticancer drugs, Etoposide (hTopo-II inhibitor) and 5-Flurouracile (5-FU). [ABSTRACT FROM AUTHOR]

Herein, we report a Pd(0)-catalyzed cascade reaction of intramolecular indolyl isocyanide-insertion, isocyanide-initiated scaffold-rearrangement with indolyl migration and redox-neutral process, which affords an efficient access to indolylisoindolinones. Isocyanide as a C(sp3)H–N synthon and the alkyl motif of isocyanide as a hydride source have been explored for the first time. [ABSTRACT FROM AUTHOR]

[Display omitted] • Natural product-inspired scaffold-hopped analogues of Rutaecarpine were prepared. • A new synthetic approach enabled an effective access to the analogues. • Analogues exhibited good antiproliferative activity in various cancer cells. • Analogue 11b possess suitable physicochemical properties. • Analogue 11b did not show medicinal chemistry structural alerts PAINS and Brenk. Natural products as starting templates have shown historically major contribution to development of drugs. Inspired by the structure–function of an anticancer natural alkaloid Rutaecarpine, the Scaffold-hopped Acyclic Analogues of Rutaecarpine (SAAR) with 'N'-atom switch (1°-hop) and ring-opening (2°-hop) were investigated. A new synthetic route was developed for an effective access to the analogues, i.e. 2-indolyl-pyrido[1,2- a ]pyrimidinones, which involved preparation of N -Boc- N'- phthaloyltryptamine/mexamine-bromides and pyridopyrmidinon-2-yl triflate, a nickel/palladium-catalysed Ullmann cross-coupling of these bromides and triflate, deprotection of phthalimide followed by N -aroylation, and Boc-deprotection. Fourteen novel SAAR-compounds were prepared, and they showed characteristic antiproliferative activity against various cancer cells. Three most active compounds (11a , 11b , and 11c) exhibited good antiproliferative activity, IC 50 7.7–15.8 µM against human breast adenocarcinoma cells (MCF-7), lung cancer cells (A549), and colon cancer cells (HCT-116). The antiproliferative property was also observed in the colony formation assay. The SAAR compound 11b was found to have superior potency than original natural product Rutaecarpine and an anticancer drug 5-FU in antiproliferative activities with relatively lower cytotoxicity towards normal breast epithelial cells (MCF10A) and significantly higher inhibitory effect on cancer cells' migration. The compound 11b was found to possess favourable in silico physicochemical characteristics (lipophilicity-MLOGP, TPSA, and water solubility-ESOL, and others), bioavailability score, and pharmacokinetic properties (GI absorption, BBB non-permeant, P-gp, and CYP2D6). Interestingly, the compound 11b did not show any medicinal chemistry structural alert of PAINS and Brenk filter. The study represents for the first time the successful discovery of new potent anticancer chemotypes using Rutaecarpine natural alkaloid as starting template and reaffirms the significance of natural product-inspired scaffold-hopping technique in drug discovery research. [ABSTRACT FROM AUTHOR]

A (4+1)‐annulation of arylidene heterocyclic‐N‐fused imidazolones with α‐carbonyl sulfoxonium ylides has been developed. The reaction enabled efficient access to a range of N‐heterocycle‐fused furans, such as secondary hydroxyl and the structural parts of drug/bioactive compounds. A unique triple‐role of α‐carbonyl sulfoxonium ylides and a characteristic stereo‐electronic functional behavior of the arylidene N‐fused imidazolones have been explored. [ABSTRACT FROM AUTHOR]

The use of zinc tetrafluoroborate as a catalyst in Mannich-type addition of silyl enol ethers to aldimines in aqueous THF provides β-amino ketones or β-amino esters in high yields. A one-pot reaction of an aldehyde, amine and silyl enolate also works well. [Copyright &y& Elsevier]

Examines the selective reduction of terminal alkynes to alkenes by indium metal. Reduction of an acetylenic triple bond to an olefinic double bond by indium metal; Provision of corresponding allyl compound by extraction of ether; Features of the reduction procedure.

In academia as well as the intensely competitive pharmaceutical industry, it is critical to offer innovative hypotheses, methodologies and technologies that can shorten the drug research and development and provide higher success. In this article, we have demonstrated how innovative variations of scaffold hopping strategy have facilitated to successfully create new druggable molecular spaces, (1) drug to drug, clinical or preclinical candidates, (2) clinical candidates to clinical or preclinical candidates, and (3) bioactive agents to clinical candidates. This review also provides an analysis of molecular modulations that enabled improvement in the pharmacodynamics, physiochemical and pharmacokinetic properties (P3-properties). [Display omitted] • Molecular medicinal properties: Pharmacodynamics, physiochemical and pharmacokinetic properties (P3-properties). • Successful innovation: Drug to drug, Drug to clinical candidate, Clinical candidate to, clinical candidate, Clinical candidate to new agent, Bioactive agent to clinical candidate and Drug to new agent. • Advance synthetic methods: Molecular editing, insertion of functional motif, and an important innovative-path of drug discovery with rational integration of advance synthetic method and P3-properties. In both academia and the pharmaceutical industry, innovative hypotheses, methodologies and technologies that can shorten the drug research and development, leading to higher success rates, are vital. In this review, we demonstrate how innovative variations of the scaffold-hopping strategy have been used to create new druggable molecular spaces, drugs, clinical candidates, preclinical candidates, and bioactive agents. We also analyze molecular modulations that enabled improvements of the pharmacodynamic (PD), physiochemical, and pharmacokinetic (PK) properties (P3 properties) of the drugs resulting from these scaffold-hopping strategies. [ABSTRACT FROM AUTHOR]

A strategy of scaffold-hopping of bioactive natural products, flavones and isoflavones, leading to target-based discovery of potent anticancer agents has been reported for the first time. Scaffold-hopped flavones, 2-aryl-4 H -pyrido[1,2- a ]pyrimidin-4-ones and the scaffold-hopped isoflavones, 3-aryl-pyrido[1,2- a ]pyrimidin-4-ones were synthesized via Pd-catalyzed activation–arylation methods. Most of the compounds were found to exhibit pronounced human topoisomerase IIα (hTopoIIα) inhibitory activities and several compounds were found to be more potent than etoposide (a hTopoII α -inhibiting anticancer drug). These classes of compounds were found to be hTopoII α -selective catalytic inhibitors while not interfering with topoisomerase I and interacted with DNA plausibly in groove domain. Cytotoxicities against various cancer cells, low toxicity in normal cells, and apoptotic effects were observed. Interestingly, compared to parent flavones/isoflavones, their scaffold-hopped analogs bearing alike functionalities showed significant/enhanced hTopoII α -inhibitory and cytotoxic properties, indicating the importance of a natural product-based scaffold-hopping strategy in the drug discovery. [ABSTRACT FROM AUTHOR]

CYP1A1 is a potential target for anticancer drug development due to its overexpression in certain cancer cells and role in cancer progression. To identify new leads for CYP1A1 mediated anticancer action, we attempted ligand based pharmacophore mapping, virtual screening of databases, molecular docking, MetaSite based filtering, and molecular dynamics simulations. Initial computational and in vitro screening identified 11 compounds from which we identified two lead compounds, ZINC33468944 and ZINC32101539, showed potential antitumor activity on MDA-MB-435 cell lines (GI 50 < 0.1 μM) and CYP1A1 inhibition of 0.13 and 0.3 μM, respectively. Furthermore, the lead compounds were evaluated for CYP1A1 mediated metabolism, showing N-hydroxylated metabolites, which have potential of DNA adduct formation and cause cancerous cell death. Analysis of molecular dynamics simulations provided important guidelines for the further modification of the lead compounds. Hence, we claim the lead molecules for further development in anticancer drug discovery. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Explores the stereoselective reduction of aryl-substituted gem-dibromides to vinyl bromides by indium metal. Importance of the vinyl bromides in organic synthesis; Employment of the Wittig aldehyde olefination; Results of indium-mediated reduction.

[Display omitted] • "Nature-to-new" as a medicinal chemistry strategy. • Iterative Scaffold-hopping to identify new chemotype. • Organocatalysed Umpolung Chemistry to construct Arylidene heterocyclic-fused imidazolone scaffold. • Polyphosphoric acid-mediated ester-lactam exchange. • In silico study reveals good drug-like properties. A strategy of "Nature-to-new" with iterative scaffold-hopping was considered for investigation of privileged ring/functional motif-elaborated analogs of natural aurones. An organocatalyzed umpolung chemistry based method was established for molecular-diversity feasible synthesis of title class of chemotypes i.e. (Z)-2-Arylideneimidazo[1,2– a ]pyridinones and (Z)-2-Arylidenebenzo[ d ]imidazo[2,1–b]thiazol-3-ones. Various biophysical experiments indicated their important biological properties. The analogs showed characteristic anticancer activities with efficiency more than an anticancer drug. The compounds induced apoptosis with arrest in the S phase of the cell cycle regulation. The compounds' significant effect in up/down-regulation of various apoptotic proteins, an apoptosis cascade, and the inhibition of topoisomerases-mediated DNA relaxation process was identified. The analysis of the structure-activity relationship, interference with biological events and the drug-likeness physicochemical properties of the compounds in the acceptable window indicated distinctive medicinal molecule-to-properties of the investigated chemotypes. [ABSTRACT FROM AUTHOR]

Abstract: Based on known heterocyclic topoisomerase II inhibitors and anticancer agents, various indenoindolone derivatives were predicted as potential topoisomerase II–inhibiting anticancer agents. They are hydrazones, (thio)semicarbazones, and oximes of indenoindolones, and indenoindolols. These derivatives with suitable substitutions exhibited potent specific inhibition of human DNA TopoIIα while not showing inhibition of topoisomerase I and DNA intercalation, despite the fact that parent indenoindolones are known poor/moderate inhibitors of topoisomerase II. The potent topoisomerase II inhibitor indenoindolone derivatives exhibited good anticancer activities compared to etoposide and 5-fluorouracil, and relatively low toxicity to normal cells. These derivatizations of indenoindolones were found to result in enhancement of anticancer activities. [Copyright &y& Elsevier]

A novel one-pot synthesis of polysubstituted oxa(thia)zolidin-2-imines has been developed. It employs A3-coupling of aldehyde and amine with alkyne to form propargyl amine, which on (thio)amidation with iso(thio)cyanate produces N-propargyl( thio)urea, and a cyclization reaction. A 5-exo-dig iodocyclization of N-propargylurea constructs 5-iodomethyleneoxazolidin-2- imine, while cycloisomerization of the thio analogue provides 5- methylenethiazolidin-2-imine. In this process, CuI catalysis has been found to be crucial, and the cyclization occurs through oxygen/ sulfur (not nitrogen) nucleophilic attack to alkyne. [ABSTRACT FROM AUTHOR]

Abstract: Scaffold hybridization of several natural and synthetic anticancer leads led to the consideration of indenoindolones as potential novel anticancer agents. A series of these compounds were prepared by a diversity-feasible synthetic method. They were found to possess anticancer activities with higher potency compared to etoposide and 5-fluorouracil in kidney cancer cells (HEK 293) and low toxicity to corresponding normal cells (Vero). They exerted apoptotic effect with blocking of cell cycle at G2/M phase. [Copyright &y& Elsevier]

[Display omitted] Two series of (hetero)arylamino-naphthoquinones and benzo-fused carbazolequinones were considered for study with the rationale that related structural motifs are present in numerous drugs, clinical trial agents, natural products and hTopoIIα inhibitors. Total 42 compounds were synthesized by reactions including dehydrogenative C N and Pd-catalyzed C C bond forming transformations. These compounds were screened against numerous cancer cells including highly metastatic one (MCF-7, MDA-MB-231, H-357 and HEK293T), and normal cells (MCF 10A). Some of the active compounds were evaluated for clonogenic cell survival and apoptotic effects in cancer cells (DAPI nuclear staining, Comet assay, Annexin-V-FITC/PI dual staining, flow cytometry, and western blot analysis with relevant proteins). All compounds were tested for hTopoIIα inhibitory activity. The investigated series compounds showed important properties like significant apoptotic antiproliferation in cancer cells with cell cycle arrest at S-phase and downregulation of NF- κβ signaling cascade, relatively less cytotoxicity to normal cells, and hTopoIIα inhibition with more efficiency compared to an anticancer drug etoposide. [ABSTRACT FROM AUTHOR]

An aberrant accumulation of nuclear β-catenin is closely associated with the augmentation of cancer malignancy. In this work, we report that several microtubule-targeting agents (MTAs) such as vinblastine, taxol, and C12 (combretastatin-2-aminoimidazole analog) inhibit Wnt/β-catenin signaling in oral squamous cell carcinoma (OSCC). We showed that the inhibition of microtubule dynamics by MTAs decreased the level of β-catenin by increasing Axin and adenomatous polyposis coli levels and reducing the level of dishevelled. Furthermore, MTAs strongly reduced the localization of β-catenin in the nucleus. The reduction in the level of nuclear β-catenin was neither due to the degradation of β-catenin in the nucleus nor due to an increase in the export of nuclear β-catenin from the nucleus. A motor protein kinesin-2 was found to assist the nuclear transportation of β-catenin. Interestingly, Wnt/β-catenin signaling antagonist treatment synergized with MTAs and the activators of Wnt/β-catenin signaling antagonized with the MTAs. C12 potently suppressed the growth of 4-Nitroquinoline 1-oxide-induced OSCC in the tongue of C57 black 6 mice and also abrogated Wnt/β-catenin signaling pathway in the tumor. Our results provide evidence that the decrease in Wnt/β-catenin signaling is an important antitumor effect of MTAs and the combined use of MTAs with Wnt/β-catenin signaling antagonists could be a promising strategy for cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Combretastatin A4 and its analogs are undergoing various clinical trials for the treatment of different cancers. This study illustrated the molecular mechanism and antitumor activity of C12, (5-Quinolin-3-yl and 4-(3,4,5-trimethoxyphenyl) substituted imidazol-2-amine), a synthetic analog of CA-4. C12 reduced the tumor volume of MCF-7 xenograft in NOD-SCID mice without affecting the bodyweight of the mice. Further, C12 inhibited the proliferation of several types of cancer cells more efficiently than their noncancerous counterparts. Using GFP-EB1 imaging, the effects of C12 on the interphase microtubule dynamics were determined in live HeLa cells. C12 (10 nM, half-maximal proliferation inhibitory concentration) reduced the growth rate of microtubules by 52% and increased the pause time of microtubules by 68%. In addition, fluorescence recovery after photobleaching analysis demonstrated that 10 nM C12 strongly suppressed spindle microtubule dynamics in HeLa cells. C12 treatment reduced the interpolar distance between the two spindle poles, increased the chromosome congression index, inhibited chromosome movement, and increased the level of mitotic checkpoint complex proteins BubR1 and Mad2. The evidence presented here indicated that C12 could induce different modes of cell death, depending on the extent of microtubule depolymerization. Since C12 targets both the mitotic and non-mitotic cells and showed a stronger activity against cancerous cells than non-cancerous cells, it may have an advantage in cancer chemotherapy. The results significantly enhance our understanding of the antitumor mechanism of the microtubule-depolymerizing agents. [ABSTRACT FROM AUTHOR]

The three-component reaction of aldehydes, amines and phenylacetylene is followed by amidation with isocyanates and iodocyclization to produce the oxazole systems. [ABSTRACT FROM AUTHOR]