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Disclosed are compounds of the formula: wherein R8 represents a cyclic moiety to which is bound an imodazolylalkyl group; R9 represents a carbamate, urea, amide or sulfonamide group; and the remaining substituents are as defined herein. Also disclosed is a method of treating cancer and a method of inhibiting farnesyl protein transferase using the disclosed compounds

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Reference:
Isoquinoline – Wikipedia,
Isoquinoline | C9H941N – PubChem

 

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Organotin-aided three component couplings of C=N double bonds with 2,4-pentadienyl and alpha,beta-unsaturated acyl groups followed by intramolecular Diels-Alder reactions result in highly stereoselective bicycloannulation of the C=N double bonds to afford allo-berbane and allo-yohimbane systems in one-flask operation.

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Isoquinoline – Wikipedia,
Isoquinoline | C9H978N – PubChem

 

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Selective targeting of cancer cells over normal cells is a key objective of targeted therapy. However few approaches achieve true mechanistic selectivity resulting in debilitating side effects and dose limitation. In this work we describe the discovery of A131 (4a), a new agent with an unprecedented dual mechanism of action targeting both mitosis and autophagy. Compound 4a was first identified in a phenotypic screen in which HeLa cells treated with 4a manifested mitotic arrest along with formation of multiple vesicles. Further investigations showed that 4a causes an increase in mitotic marker pH3 and autophagy marker LC3. Importantly 4a induces cell death in cancer cells while sparing normal cells which regrow after 4a is removed. Dual activities against pH3 and LC3 markers are required for cancer cell selectivity. An extensive SAR investigation confirmed 4a as the optimal dual inhibitor with potency against a panel of 30 cancer cell lines (average antiproliferative GI50 1.5 muM). In a mouse model of paclitaxel-resistant colon cancer, 4a showed 74% tumor growth inhibition when administered at a dose of 20 mg/kg IP twice a day.

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Reference:
Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem

 

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Simple enantiomerically pure C2-symmetric quinoline (isoquinoline)-derived 1,2-diamines were synthesized from the corresponding aldehydes via stereospecific diaza-Cope rearrangement with 2,2?-(1,2-diaminoethane-1,2-diyl)diphenol (HPEN). Efficient green synthesis of both enantiomers of the anticoagulant Warfarin and rodenticide Coumachlor was achieved in an aqueous medium via the asymmetric iminium-type Michael reaction in the presence of the catalysts 8e and (ent)-8e in combination with (R)- or (S)-mandelic acid, respectively. This procedure provides high enantioselectivity (up to 91% ee), which has never been attained for these bioactive compounds with the known catalysts under aqueous conditions. Nearly optically pure Warfarin (?99% ee) was prepared via a green isolation procedure, which included acidic precipitation of the crude product from a basic aqueous solution followed by single recrystallization. Furthermore, unlike the known primary amine-derived organocatalysts, the developed aqueous catalytic system does not produce parasitic byproducts and can be recovered and reused in the asymmetric reaction.

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Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem

 

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A unique reactivity of a nitrile-stabilized quaternary ammonium ylide as a masked C-CN 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.

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Reference:
Isoquinoline – Wikipedia,
Isoquinoline | C9H955N – PubChem

 

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A new series of IGF-1R inhibitors related to hydantoins were identified from a lead originating from HTS. Their noncompetitive property as well as their slow binding characteristics provided a series of compounds with unique selectivity and excellent cellular activities.

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Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem

 

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Isoquinoline-4-aldehydes of the formula STR1 in which X denotes bromine or chlorine, R1 is phenyl optionally mono- or disubstituted by halogen, hydroxy, nitro, amino, or amino substituted by one or two aliphatic, cycloaliphatic or aromatic hydrocarbon radicals having from 2 to 18 carbon atoms, the nitrogen atom possibly being included in a heterocyclic ring, acyl amino, alkyl or alkoxy each having from 1 to 6 carbon atoms, benzoyloxy, or trifluoromethyl, or is pyridyl or thienyl; R2 is hydrogen, halogen, hydroxy, alkyl or alkoxy having from 1 to 6 carbon atoms, nitro, amino, benzyloxy, methylene dioxy or ethylene dioxy and m is 1 or 2; which are effective in the treatment of spasms and as tranquilizers.

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Isoquinoline – Wikipedia,
Isoquinoline | C9H936N – PubChem

 

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We demonstrate that the Knoevenagel condensation can be exploited in combinatorial synthesis on the solid phase. Condensation products from such reactions were structurally characterized, and their Michael reactivity with thiol and phosphine nucleophiles is described. Cyanoacrylamides were previously reported to react reversibly with thiols, and notably, we show that dilution into low pH buffer can trap covalent adducts, which are isolable via chromatography. Finally, we synthesized both traditional and DNA-encoded one-bead, one-compound libraries containing cyanoacrylamides as a source of cysteine-reactive reversibly covalent protein ligands.

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Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem

 

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Difficulties in developing active-site-directed protein tyrosine phosphatase (PTP) inhibitors have led to the perception that PTPs are “undruggable”, highlighting the need for new means to target pharmaceutically important PTPs allosterically. Recently, we characterized an allosteric-inhibition site on the PTP domain of Src-homology-2-domain-containing PTP 2 (SHP2), a key anticancer drug target. The central feature of SHP2’s allosteric site is a nonconserved cysteine residue (C333) that can potentially be labeled with electrophilic compounds for selective SHP2 inhibition. Here, we describe the first directed discovery effort for C333-targeted allosteric SHP2 inhibitors. By screening a previously reported library of reversible, covalent inhibitors, we identified a lead compound, which was modified to yield an irreversible inhibitor (12), that inhibits SHP2 allosterically and selectively through interaction with C333. These findings provide a novel paradigm for allosteric-inhibitor discovery on SHP2, one that may help to circumvent the challenges inherent in targeting SHP2’s active site.

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Isoquinoline – Wikipedia,
Isoquinoline | C9H965N – PubChem

 

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A new class of simple synthetic antimitotic compounds based on 2-aroylindoles was discovered. (5-Methoxy-1H-2-indolyl)-phenylmethanone (1) as well as analogous 3-fluorophenyl- (36) and 3-methoxyphenyl (3) derivatives displayed high cytotoxicity of IC50 = 20 to 75 nM against the human HeLa/KB cervical, SK-OV-3 ovarian, and U373 astrocytoma carcinoma cell lines. The inhibition of proliferation correlated with the arrest in the G2/M phase of the cell cycle. In in vitro assays with tubulin isolated from bovine brain, in general antiproliferative activity correlated with inhibition of tubulin polymerization. Thus, the antimitotic activity of 2-aroylindoles is explained by interference with the mitotic spindle apparatus and destabilization of microtubules. In contrast to colchicine, vincristine, nocodazole, or taxol, 1 did not significantly affect the GTPase activity of beta-tubulin. Interestingly, selected compounds inhibited angiogenesis in the chorioallantoic membrane (CAM) assay. In xenograft experiments, 1 was highly active after oral administration at 200 mg/kg against the human amelanocytic melanoma MEXF 989 in athymic nude mice. We conclude, that 2-aroylindoles constitute an interesting new class of antitubulin agents with the potential to be clinically developed for cancer treatment.

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Reference:
Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem