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In the rapidly expanding era of cancer target therapy, regulators of apoptosis are emerging as attractive therapeutic targets. X-linked inhibitor of apoptosis (XIAP) is of specific interest owing to its characteristic overexpression in a wide variety of neoplasms, with a resultant survival advantage for tumor cells and treatment resistance. In this study, we examined three pyrazolo [3,4-d] pyridazine derivatives (PPDs) through molecular modeling and studied their modes of interaction with XIAP-BIR3 domain. PPD-1, which possessed the highest binding affinity with XIAP, was tested on A549 (lung cancer cell line); HCT-116 (colorectal carcinoma cell line); HEPG2 (liver carcinoma cell line), HFB4 (normal human skin melanocyte cell line) and WI-38 (human embryonic lung fibroblasts). In comparison to cisplatin as a positive control, PPD-1 yielded remarkable cytotoxicity on all cancer cell lines, with the highest anti-tumor activity on A549 and a favorable therapeutic ratio. Flow cytometry studies concluded that PPD-1 treatment induces Sub G1 and G2/M cell cycle arrest and apoptosis. The percentage of apoptotic cells in PPD-1 treated A549 cells was considerably higher than that in untreated cells (10.06% vs 0.57%, respectively). To further investigate the mechanism of induction of apoptosis by PPD-1, Real time-PCR was used to quantify the expression levels of key apoptotic regulators. Significant overexpression of the effector capsase-3, pro-apoptotic bax and tumor suppressor gene p53 were noted as compared to untreated cells (7.19 folds, 7.28 folds, and 5.08 folds, respectively). Moreover, PPD-1 inhibited the expression of the anti-apoptotic bcl-2 gene to 0.22 folds. These findings demonstrate that PPD-1 treatment disrupts the Bcl-2/BAX balance in lung cancer cell lines, leading to apoptosis induction possibly through intrinsic mitochondria-dependent pathway. These novel insights elucidate the mechanism of PPD-1 cytotoxicity in lung cancer cell lines and offer a promising therapeutic approach that needs further study., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

2,3-Dihydro-2-oxo-4-phenyl-6-(thien-2-yl)pyridine-3-carbonitrile (4) was synthesized via reaction of four compounds (benzaldehyde, 2-acetylthiophene, ethyl cyanoacetate and ammonium acetate) in one step reaction. 2-((Hydrazinocarbonyl)methyloxy)-4-phenyl-6-(2-thienyl)pyridine-3-carbonitrile was obtained by reaction of 5 with hydrazine hydrate. Schiff's bases, pyrazole derivatives, urea derivatives, and carbamates were also synthesized. Based on the spectral facts and elemental analysis, structures of the newly synthesized compounds were elucidated. Also, the new compounds were evaluated for their antibacterial and antitumor activities. [ABSTRACT FROM AUTHOR]

Sodium salt of 3‐hydroxy‐1‐(1‐aryl‐5‐methylpyrazolyl)propenone derivatives was used as a precursor for synthesis of various fused azolopyrimidine ring systems as pyrazolopyrimidines, triazolopyrimidines, and pyrimidobenzimidazoles following many procedures. The identity of the prepared compounds was elucidated by their spectral data and elemental analyses. The in vitro antimicrobial activity of 13 new compounds was evaluated, and many derivatives showed good to moderate activity. [ABSTRACT FROM AUTHOR]

Three novel series of nitroso derivatives (11 – 15 ), isoxazolopyrazoles ( 17a – c ) and isoxazolo[3,4- d ]pyridazines (18a – c ) were prepared from the hydroxyimoyl chloride 10 . In vitro COX1⧹2 inhibition activities were evaluated, both of 17b and 18a proved a promising inhibitory activity with IC 50 = 1.12, 0.78 μM in sequent . Carrageenan induced Paw edema, ulcer liability, nitric oxide (NO ) release and histopathological study were determined. Most of the prepared compounds showed excellent activities. Reactions of 2-aminopyridine and enaminone with hydroxyimoyl chloride 10 were investigated and proved by 2D NMR. Molecular docking for most active compounds was operated giving a hint for compound–receptor interactions . [ABSTRACT FROM AUTHOR]

A series of new 5-(heteroaryldiazenyl)thiazole incorporating pyrazole moiety have been synthesized through coupling of the thiazole with the appropriate heteroaryldiazonium salts. The newly synthesized compounds were characterized by elemental analysis, spectroscopic (IR, 1H NMR, and Mass) data, and alternative synthesis whenever possible. [ABSTRACT FROM AUTHOR]

2-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-N′-phenylaceto-hydrazonoyl bromide was synthesized and used as precursor for synthesis of some new 1,3,4-thiadiazoles, pyrrolo[3,4-c]pyrazoles, and 1,2,4-triazolo[4,3-a]pyrimidines. The mechanisms that account for formation of products were discussed. Also, the structures of all the newly synthesized products were confirmed based on elemental analysis, spectral data and by alternative methods. [ABSTRACT FROM AUTHOR]

Pyrazolo[3,4- d]pyridazines, isoxazolo[3,4- d]pyridazines, azolo[1,5- a]pyrimidines, azolo[5,1- c]triazines, pyrazoles, and benzo[ b][l,4]diazepine were synthesized from the appropriate hydrazonoyl halides, hydroximoyl halides, heterocyclic amines, diazotized heterocyclic amines, arenediazonium chlorides, and o-phenylenediamines with appropriate of sodium 3-(5-bromobenzofuran-2-yl)-3-oxoprop-1-en-1-olate or 1-(5-bromobenzofuran-2-yl)-3-(dimethylamino)prop-2-en-1-one. The newly synthesized compounds were elucidated by elemental analyses, spectral data, and alternative synthesis whenever possible. [ABSTRACT FROM AUTHOR]

2-(3-(1H-Indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-substituted-5-(substituted diazenyl)thiazoles and 2-(1H-indol-3-yl)-9-substituted-4,7-disubstituted pyrido[3,2-e][1,2,4]triazolo [4,3-a]pyrimidin-5(7H)-ones were synthesized via reaction of hydrazonoyl halides with each of 3-(1H-indol-2-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide and 7-(1H-indol-3-yl)-2- thioxo-5-substituted-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones, respectively. Also, hydrazonoyl halides were reacted with N’-(1-(1H-indol-3-yl)ethylidene)-2-cyanoacetohydrazide to afford 1,3,4-thiadiazole derivatives. Structures of the new synthesis were elucidated on the basis of elemental analysis, spectral data, and alternative synthetic routes whenever possible. Fifteen of the new compounds have been evaluated for their antitumor activity against the MCF-7 human breast carcinoma cell line. The results indicated that many of the tested compounds showed moderate to high anticancer activity when compared with doxorubicin as a reference drug. [ABSTRACT FROM AUTHOR]

Condensation of sodium 3-oxo-3-(1-phenyl-1H-pyrazol-4-yl)prop-1-en-1-olate (2) with several heterocyclic amines, cyanoacetamide, cyanothioacetamide, and 2-cyanoacetohydrazide gives pyrazolo[1,5-a]pyrimidines (5a-d), pyrido[2',3':3,4]pyrazolo[1,5- a]pyrimidine (9), benzo[4,5]imidazo[1,2-a]pyrimidine (10), [1,2,4]triazolo[1,5-a]pyrimidine (11), and pyridine derivatives (12-14). Also, thieno[2,3-b]pyridines (15-18) were synthesized via pyridinethione (13) with α-halo ketones and α-halo ester. Structures of the newly synthesized compounds were elucidated by elemental analysis, spectral data, alternative synthetic routes, and chemical transformation whenever possible. [ABSTRACT FROM AUTHOR]

Abstract: Pyrrolo[3,4-c]pyrazole-4,6(1H,5H)-dione, pyrano[2,3-c]pyrazole-5-carbonitrile, pyrano[2,3-d]4-imidazolines, pyrido[2,1-b]benzimidazole, pyrido[2,1-b][1,3]benzoxazole, pyrido[2,1-b][1,3]benzothiazole and pyrido[2,1-b]quinazoline were synthesised from antipyrine derivatives with appropriate reagents such as maleimides, malononitrile, ethyl cyanoacetate, benzimidazole-2-acetonitrile, benzothiazole-2-acetonitrile, benzoxazol-2-acetonitrile, benzoylacetonitrile and other reagents. The newly synthesised compounds were established by elemental analysis, spectral data, and alternative synthetic routes whenever possible. [Copyright &y& Elsevier]

2-[1,2-Diaza-3-(2,3-dimethyl-5-oxo-1-phenyl(3-pyrazolin-4-yl))prop-2-enylidene]-3-phenyl-5-substituted 1,3,4-thiadiazolines and 2-{[4-(2,3-dimethyl-5-oxo-1-phenyl(3-pyrazolin-4-yl))(1,3-thiazol-2-yl)]cyanomethylene}-3-phenyl-5-substitu- ted 1,3,4-thiadiazolines were synthesized from hydrazonoyl halides and 4-{-2-aza-2-[(methylthiothioxomethyl)amino]vinyl}-2,3-dimethyl-1-phenyl-3-pyrazoin-5-one and 2-[4-(2,3-dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl)-1,3-thiazol-2-yl]ethane-nitrile, respectively. All synthesize compounds were elucidated by elemental analysis, spectra, and alternative synthesis routes, whenever possible. [ABSTRACT FROM AUTHOR]

1,3,4-Thiadiazolines containing a chromone moiety and 5-{1-[4-substituted-5-phenyldiazenyl)(1,3-thiazol-2-yl]-5-phenyl-2-pyrazolin-3-yl)}-4-methoxybenzo[b]-furan-6-ol were synthetic from hydrazonoyl halide and alkyl carbodithioates and 5-[1-aminothiomethoxy)-5-phenyl-2-pyrazolin-3-yl)]-4-methoxybenzo[b]furan-6-ol, respectively. All structures of the newly synthesized compounds were elucidated by elemental analysis, spectral data, and alternative synthesis methods whenever possible. [ABSTRACT FROM AUTHOR]

An abstract of the article "Design and Synthesis of Some New Pyrazolo[1,5-a]pyrimidines, Pyrazolo[5,1-c]triazines, Pyrazolo[3,4-d]pyridazines, and Isoxazolo[3,4-d]pyridazines Containing the Pyrazole Moiety" by Abdou O. Abdelhamid, Abdelgawad A. Fahmi and Karema N. M. Halim is presented.

A variety of the title compounds (III) and (IV), resp., are synthesized and screened for their in vitro antitumor activities against HCF-7. [ABSTRACT FROM AUTHOR]