Substituted benzimidazoles: A novel chemotype for small molecule hKSP inhibitors

Lahue, Brian R.; Ma, Yao; Shipps, Gerald W.; Seghezzi, Wolfgang; Herbst, Ronald

doi:10.1016/j.bmcl.2009.05.040

Cited by 23 publications

(20 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Benzimidazoles are described as inhibitors of the kinesin spindle protein (KSP) (Lahue et al, 2009), hypoxia-inducible factor (HIF-1) (Won et al, 2009), the enzyme 17α-hydroxylase/17,20 (Bruno et al, 2008), and others (Bhattacharya et al, 2010), which are important targets for the development of new anticancer drugs. The derivatives of bis-benzimidazoles are inhibitors of DNA topoisomerase I (Kazimierczuk and Shugar, 1989;Kraut et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of novel 4-(1H-benzimidazol-2-yl)benzene-1,3-diols and their cytotoxic activity against human cancer cell lines

2011

View full text Add to dashboard Cite

One-pot synthesis of new biologically active 4-(1H-benzimidazol-2-yl)benzene-l,3-diols has been developed. The compounds were prepared by the reaction of aryl-modified sulfinylbis[(2,4-dihydroxyphenyl)methanethione]s with benzene-l,2-diamines. Their structures were identified using elemental, IR, (1)H-NMR, and mass spectra analyses. The developed method offers short reaction times, relatively large-scale synthesis, easy and quick isolation of the products, and good yields. The cytotoxicity in vitro against the 4 human cancer cell lines: SW707 (rectal), HCV29T (bladder), A549 (lung), and T47D (breast) was determined. The antiproliferative properties of some compounds studies were stronger than those of cisplatin, which was used as a comparator drug.

show abstract

Section: Introductionmentioning

confidence: 99%

Synthesis of novel 4-(1H-benzimidazol-2-yl)benzene-1,3-diols and their cytotoxic activity against human cancer cell lines

2011

View full text Add to dashboard Cite

show abstract

“…para-MeO substitution of the phenyl group (17) afforded a compound comparable to 1 in potency and selectivity. Additional substitution of a methyl (18) or methoxy (19) group at the meta position resulted in a potency decrease of 7-fold. Bridging the two oxygen atoms at the 3-and 4-position of the phenyl group through either one carbon (20) or three carbons (21) gave compounds with potency 2-fold less than compound 1.…”

mentioning

confidence: 99%

Discovery of a Novel Series of CHK1 Kinase Inhibitors with a Distinctive Hinge Binding Mode

Huang

Cheng

Fischmann

et al. 2012

ACS Med. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

A novel series of CHK1 inhibitors with a distinctive hinge binding mode, exemplified by 2-aryl-N-(2-(piperazin-1-yl)phenyl)thiazole-4-carboxamide, was discovered through high-throughput screening using the affinity selection−mass spectrometry (AS-MS)-based Automated Ligand Identification System (ALIS) platform. Structure-based ligand design and optimization led to significant improvements in potency to the single digit nanomolar range and hundred-fold selectivity against CDK2.KEYWORDS: affinity selection−mass spectrometry (AS-MS), Automated Ligand Identification System (ALIS), CHK1 protein kinase, structure-based drug design, thiazole-4-carboxamide C ancer is the leading cause of death globally. 1 Among the treatments used in cancer clinics, DNA-damaging chemotherapies have received widespread use despite their severe side effects on highly proliferative tissues and vulnerability to drug resistance. 2 There is an urgent need in cancer therapy for improved tolerability and longer lasting efficacy. When cells are exposed to agents that induce DNA damage, DNA repair pathways are activated by arresting at various cell cycle check points, G1, S, and G2/M. 3 While normal cells could arrest in the G1 phase through the tumor suppressor protein p53, most cancer cells lack this option because of p53 mutations and will have to rely on the S or G2/M checkpoint for DNA repair and survival. Such reliance in p53 mutant cancer cells would offer a significant opportunity for targeted cancer therapy. 4 CHK1 (checkpoint kinase 1) is a serine/threonine kinase and the key mediator in S and G2/M checkpoints. 5 The abrogation of CHK1 and the remaining checkpoints consequentially will cause cancer cells with DNA damage premature entry into mitosis and result in cell death. 6 Therefore, an enlarged therapeutic window would be expected in anticancer therapies utilizing a combination of a DNA-damaging agent with a CHK1 inhibitor.Over the past years, extensive research efforts in CHK1 inhibition have been undertaken in oncology. Several small molecule CHK1 inhibitors have been discovered and entered into clinical trials. 7−11 In our efforts to discover novel small molecule CHK1 inhibitors, the AS-MS ALIS (affinity selection−mass spectrometry-based Automated Ligand Identification System) platform was used to identify hits from mixture-based combinatorial libraries. 12 ALIS has demonstrated its unique capability in screening label-free mixture-based libraries and finding hits that were subsequently developed into lead compounds in various classes of protein targets, including the anti-infective target Escherichia coli dihydrofolate reductase, 13 antibacterial AccC (acetyl coenzyme-A carboxylase), 14 HCV NS5B (hepatitis C virus nonstructural protein 5B) polymerase, 15−17 protein kinase CDK2 (cyclin-dependent kinase 2), 18 KSP (kinesin spindle protein) in oncology, 19 FABP4 (fatty acid binding protein-4) 20 and the lipid phosphatase SHIP2 (SH2 domain-containing inositol 5-phosphatase 2) 21 in diabetes, MK2 (mitogen-activated protein ...

show abstract

“…Phenyl Sulfones 1b,c,e,f, 14 1d, 15 1i, 16 and 1j 17 and alkynes 2bed 18 were prepared according to published procedures. All starting materials and reagents were commercially available.…”

Section: Methodsmentioning

confidence: 99%

“…13 (m,4H),7.42 (dd,J¼1.2,7.6 Hz,1H),7.49 (dt,J¼1.3,7.9 Hz,1H),7.60 (dt,J¼1.4,7.4 Hz,1H),8.12 (dd,J¼1.2,8.0 Hz,1H); 13 C NMR (100 MHz, CDCl 3 ) d 21. 3,22.7,44.3,128.0,128.85,128.89,129.3,129.9,130.7,131.09,133.0,133.3,133.9,136.3,137.1,137.5,138.9,139.2,144.6;HRMS (APCI) 13.8, 22.8, 30.3, 33.2, 44.9, 127.1, 127.7, 128.4, 128.8, 129.4, 130.0, 131.8, 133.1, 136.8, 138 5, 45.0, 127.2, 127.7, 128.4,129.0,129.2,130.1,130.7,133.6,136.8,138.2,138.5,145.9; HRMS (APCI) m/z calcd for C 16 4, 44.4, 127.2, 127.7, 128.1, 128.2, 128.8, 129.4, 130.2, 130.9, 131.2, 133.6, 136.3, 136.7, 139.1, 140.1, 144. 4, 55.6, 112.8, 118.5, 127.3, 127.8, 128.1, 128.2, 129.4,130.9,131.0,131.1,132.6, 136.6, 138.8,140.0,146.3,163. Mp 58e60 C, 44 mg (41%), isolated by column chromatography using hexane/ethyl acetate (3:1, v/v); 1 H NMR (400 MHz, CDCl 3 ) d 2.45 (s, 3H), 6.71 (s, 1H), 6.97 (dd, J¼8.8, 2.6 Hz, 1H), 7.08e7.12 (m, 3H), 7.17e7. 18 (m,5H),7.21e7.26 (m,6H),7.42 (dd,J¼7.4,6.6 Hz,…”

Section: (E)-1-(2-(methylsulfonyl)phenyl)-12-diphenylethene (3a)mentioning

confidence: 99%

Rhodium-catalyzed direct ortho-alkenylation of phenyl sulfones with alkynes utilizing sulfonyl function as modifiable directing group

et al. 2015

View full text Add to dashboard Cite

a b s t r a c tThe ortho-selective alkenylation of phenyl sulfones with alkynes proceeds effectively in the presence of a cationic Cp*-rhodium(III) catalyst together with an appropriate carboxylic acid involving regioselective CeH bond cleavage directed by the sulfonyl function. An (ortho-alkenylated phenyl) methyl sulfone prepared by this hydroarylation method undergoes palladium-catalyzed a-arylation and subsequent diastereoselective cyclization to directly produce the corresponding thiochromane 1,1-dioxide derivatives.

show abstract

Substituted benzimidazoles: A novel chemotype for small molecule hKSP inhibitors

Cited by 23 publications

References 23 publications

Synthesis of novel 4-(1H-benzimidazol-2-yl)benzene-1,3-diols and their cytotoxic activity against human cancer cell lines

Synthesis of novel 4-(1H-benzimidazol-2-yl)benzene-1,3-diols and their cytotoxic activity against human cancer cell lines

Discovery of a Novel Series of CHK1 Kinase Inhibitors with a Distinctive Hinge Binding Mode

Rhodium-catalyzed direct ortho-alkenylation of phenyl sulfones with alkynes utilizing sulfonyl function as modifiable directing group

Contact Info

Product

Resources

About