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A series of benzofuro‐fused 7‐deazapurine (6H‐furo[2,3‐e]pyrimido[4,5‐b]indole) 2'‐deoxyribo‐ and ribonucleosides was designed and synthesized. The synthesis of key compound 10‐chloro‐6H‐furo[2,3‐e]pyrimido[4,5‐b]indole was based on the Negishi cross‐coupling of iodobenzofurane with zincated 4,6‐dichloropyrimidine followed by azidation and photochemical cyclization. Glycosylation of the heterocycle with either Hoffer's chlorodeoxyribose or protected ribose followed by cross‐coupling or substitution reactions at position 10 gave the desired two sets of final nucleosides that showed moderate to weak cytostatic activity and interesting fluorescence properties. [ABSTRACT FROM AUTHOR]

The combination of cytotoxic amino‐BODIPY dye and 2‐phenyl‐3‐hydroxy‐4(1H)‐quinolinone (3‐HQ) derivatives into one molecule gave rise to selective activity against lymphoblastic or myeloid leukemia and the simultaneous disappearance of the cytotoxicity against normal cells. Both species′ conjugation can be realized via a disulfide linker cleavable in the presence of glutathione characteristic for cancer cells. The cleavage liberating the free amino‐BODIPY dye and 3‐HQ derivative can be monitored by ratiometric fluorescence or by the OFF‐ON effect of the amino‐BODIPY dye. A similar cytotoxic activity is observed when the amino‐BODIPY dye and 3‐HQ derivative are connected through a non‐cleavable maleimide linker. The work reports the synthesis of several conjugates, the study of their cleavage inside cells, and cytotoxic screening. [ABSTRACT FROM AUTHOR]

The interleukin‐2‐inducible kinase (ITK) and Bruton tyrosine kinase (BTK) are two crucial Tec family kinase members with important roles in the development of hematopoietic malignancies, autoimmune disorders and other diseases in humans. Thus, ITK and BTK are key targets for drug development. Spirooxindoles are important scaffolds for the synthesis of small molecules with broad and potent biological activities. In this study, we performed a structure‐activity relationship study of a new series of 5′‐(benzo[d][1,3]dioxol‐5‐yl)spiro[piperidine‐4,3′‐pyrrolo[2,3–b]pyridin]‐2′(1′H)‐one linked with N‐acyl and C‐5 aryl‐substituted scaffolds in a panel of ITK and BTK cancer cell lines. Four compounds 11, 12, 14, and 15 showed high antiproliferative activity against ITK and BTK cell lines. Compounds 11 and 12 with a C‐5 benzodioxole group and gem‐dialkyl group attached to carbonyl on piperidine were highly effective in ITK‐high Jurkat and CEM cell lines, and compound 14, a biotin analogue, was identified as a good inhibitor of BTK‐high RAMOS cells. Compound 15 with cyclopropyl group attached to carbonyl on piperidine also showed good activity in ITK and BTK cell lines. [ABSTRACT FROM AUTHOR]

All four isomeric series of novel 4‐substituted pyrido‐fused 7‐deazapurine ribonucleosides possessing the pyridine nitrogen atom at different positions were designed and synthesized. The total synthesis of each isomeric fused heterocycle through multistep heterocyclization was followed by glycosylation and derivatization at position 4 by cross‐coupling reactions or nucleophilic substitutions. All compounds were tested for cytostatic and antiviral activity. The most active were pyrido[4′,3′:4,5]pyrimidine nucleosides bearing MeO, NH2, MeS, or CH3 groups at position 4, which showed submicromolar cytotoxic effects and good selectivity for cancer cells. The mechanism involved activation by phosphorylation and incorporation to DNA where the presence of the modified ribonucleosides causes double‐strand breaks and apoptosis. [ABSTRACT FROM AUTHOR]

Two series of substituted benzo[g]‐ or benzo[e]pyrimido[4,5‐b]indole (naphtho‐fused 7‐deazapurine) ribonucleosides were synthesized. The heterocyclic nucleobases were obtained by Negishi cross‐coupling reaction of zincated pyrimidines with naphthyl iodides, nucleophilic substitution to tetrazoles/azides and thermal cyclization or photocyclization. Nucleosides were obtained by glycosylation followed by substitution reactions and deprotection. Resulting ribonucleosides were tested for their cytotoxic activity against cancer cell lines and antiviral activities. Some derivatives showed micromolar cytotoxic activities and moderate anti‐hepatitis C virus activities. Naphtho‐fused 7‐deazapurine 2′‐deoxyribonucleoside triphosphate was successfully incorporated into DNA oligonucleotides by KOD XL DNA polymerase. Fluorescence properties of naphtho‐fused 7‐deazapurine nucleosides and oligonucleotides were also studied. Two isomeric series of bulky naphtho‐fused 7‐deazapurine nucleosides were prepared and shown to exert moderate cytostatic and antiviral activity and interesting fluorescent properties. The 2′‐deoxyribonucleoside triphosphates were substrates for KOD XL DNA polymerase. [ABSTRACT FROM AUTHOR]

Abstract: Three isomeric series of 4‐substituted thieno‐fused 7‐deazapurine nucleobases were synthesized by palladium catalyzed couplings or nucleophilic substitutions from protected key‐intermediate 4‐chlorothienopyrrolopyrimidines. Most final nucleobases exerted micromolar activity against hepatitis C virus and respiratory syncytial virus, as well as some in vitro cytostatic activities against several cancer and leukemia cell lines. Three new nucleosides derived from 8H‐thieno[3′, 4′:4,5]pyrrolo[2, 3‐d]pyrimidine were also synthesized and were significantly more cytostatic than corresponding nucleobases, with activities in submicromolar range and low toxicity to normal cycling fibroblasts. [ABSTRACT FROM AUTHOR]

Aberrant DNA methylation that results in silencing of genes has remained a significant interest in cancer research. Despite major advances, the success of epigenetic therapy is elusive due to narrow therapeutic window. A wide variety of naturally occurring epigenetic agents and synthetic molecules that can alter methylation patterns exist, however, their usefulness in epigenetic therapy remains unknown. This underlines the need for effective tumor models for large-scale screening of drug candidates with potent hypomethylation activity. In this study, we present the development of a cell-based DNA demethylation detection system, which is amenable for high content screening of epigenetic drugs in two-dimensional and three-dimensional cell culture models. Additionally, the detection system also supports the in vivo monitoring of demethylation efficacy of potential lead compounds from in vitro screens in tumor xenografts. The described detection system not only permits the continuous monitoring of demethylation but also of the induced cytostatic/cytotoxic drug effects in live cells, as a function of time. The detection system is fluorescence based and exploits the dominant ability of DNA methylation to inhibit gene transcription, and utilizes FLJ32130 gene, which is silenced on account of promoter hypermethylation in human colorectal cancer. The described work will provide the researchers with an efficient tool for epigenetic drug screens on a high throughput platform and would therefore benefit academic and industrial drug discovery. © 2016 International Society for Advancement of Cytometry [ABSTRACT FROM AUTHOR]

This work describes the synthesis of 8-iodoimidazo[1,2- c]pyrimidin-5(6 H)-one 2 from 5-iodocytosine 1. This compound was subjected to Suzuki with aryl and heteroarylboronic acids. After optimization, 10 products 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3h, 3i, 3j were obtained in good yields 61-90%. Cytotoxic activity of all new products was evaluated on seven tumor cell lines including resistant variants and on normal human fibroblasts. Two derivatives showed promising and good therapeutic index in the case of 3h. [ABSTRACT FROM AUTHOR]