Genotoxicity evaluation of a new phthalazine substituted β-lactam derivative in human lymphocytes.

The aim of present study, to evaluate the genotoxic potential of 1-(4-(3,3-dimethyl-1,6-dioxo-2,3,4,6,11,13-hexahydro-1H-indazolo[1,2b] phthalazine-13yl)phenyl)-2-phenylazetidine-3-yl-acetate which was synthesised assuming that it may be a pharmaceutical raw material and found to inhibit human carbonic anhydrase I, II isozymes. To determine the genotoxic potential of this phthalazine substituted β-lactam compound, chromosomal aberration (CA) and micronucleus (MN) tests were implemented in human peripheral blood lymphocytes. In these tests, lymphocyte cultures were treated with four concentrations (30, 15, 7.5, 3.75 μg/mL) of test compound and simultaneously with negative control (sterile distilled water), solvent control (DMSO) positive control (MMC). According to our results, CA frequencies were significantly increased in two high applied concentrations (30, 15 μg/mL) compared with negative and solvent control. MN frequencies were significantly increased in three applied concentrations (30, 15, 7.5 μg/mL) except lowest concentration (3.75 μg/mL) compared with solvent control. Mitotic indices were also affected by treatment with test compound. The obtained results provide evidence to demonstrate that new phthalazine substituted β-lactam derivative can exert genotoxic and cytotoxic effects in peripheral human lymphocytes especially at high concentrations.

[1]  R. Nanda,et al.  Synthesis and biological evaluation of Schiff’s bases and 2-azetidinones of isonocotinyl hydrazone as potential antidepressant and nootropic agents , 2016 .

[2]  I. Gulcin,et al.  The synthesis of some β-lactams and investigation of their metal-chelating activity, carbonic anhydrase and acetylcholinesterase inhibition profiles , 2016, Journal of enzyme inhibition and medicinal chemistry.

[3]  N. Berber,et al.  Synthesis and evaluation of new phthalazine substituted β-lactam derivatives as carbonic anhydrase inhibitors , 2015, Russian Journal of Bioorganic Chemistry.

[4]  D. Sharma,et al.  Synthesis of 6-(4-methanesulphonamidophenyl)-substituted dihydropyridazinone/ phthalazinone derivatives as potent anti-inflammatory and analgesic agents , 2014 .

[5]  Liying Ma,et al.  Synthesis and anticancer activities of novel 1,2,4-triazolo[3,4-a]phthalazine derivatives. , 2014, European journal of medicinal chemistry.

[6]  C. Supuran,et al.  Exploiting the hydrophobic and hydrophilic binding sites for designing carbonic anhydrase inhibitors , 2013, Expert opinion on drug discovery.

[7]  A. Aly,et al.  Synthesis of Novel Series of Phthalazine Derivatives as Potential Antitumor Agents , 2013 .

[8]  Azra Metović,et al.  Analysis of chromosome aberrations contained in vitro human peripheral blood lymphocytes after treatment with ceftriaxone. , 2013, Medical archives.

[9]  C. Supuran.  Bacterial Carbonic Anhydrases as Drug Targets: Toward Novel Antibiotics? , 2011, Front. Pharmacol..

[10]  H. Ghanem,et al.  Synthesis and Biochemical Evaluation of Some Substituted Phthalazines , 2011 .

[11]  P. Gong,et al.  Synthesis and antitumor activities of novel 1,4-disubstituted phthalazine derivatives. , 2010, European journal of medicinal chemistry.

[12]  M. Topaktaş,et al.  Cytogenetic genotoxicity of amoxicillin , 2009, Environmental and molecular mutagenesis.

[13]  M. Fahmy,et al.  In vivo Genotoxicity Studies of Cefotaxime , 2009 .

[14]  C. S. Rajput,et al.  Synthesis and anti-inflammatory activity of newer quinazolin-4-one derivatives. , 2009, European journal of medicinal chemistry.

[15]  H. Shaterian,et al.  Silica sulfuric acid as an efficient catalyst for the preparation of 2H-indazolo[2,1-b]phthalazine-triones , 2008 .

[16]  Jin Sung Kim,et al.  Synthesis of 1-/2-substituted-[1,2,3]triazolo[4,5-g]phthalazine-4,9-diones and evaluation of their cytotoxicity and topoisomerase II inhibition. , 2008, Bioorganic & medicinal chemistry.

[17]  H. Khavasi,et al.  One-pot, three-component route to 2H-indazolo[2,1-b]phthalazine-triones , 2008 .

[18]  Claudiu T. Supuran,et al.  Carbonic anhydrases: novel therapeutic applications for inhibitors and activators , 2008, Nature Reviews Drug Discovery.

[19]  X. Zhai,et al.  Synthesis and in vitro cytotoxicity of novel 1,4-disubstituted phthalazines , 2008 .

[20]  Andrea Scozzafava,et al.  Carbonic anhydrases as targets for medicinal chemistry. , 2007, Bioorganic & medicinal chemistry.

[21]  W. Au.  Usefulness of biomarkers in population studies: from exposure to susceptibility and to prediction of cancer. , 2007, International journal of hygiene and environmental health.

[22]  Brendan L Wilkinson,et al.  Carbonic anhydrase inhibitors: inhibition of isozymes I, II, and IX with triazole-linked O-glycosides of benzene sulfonamides. , 2007, Journal of medicinal chemistry.

[23]  C. Ferris,et al.  Azetidinones as vasopressin V1a antagonists. , 2007, Bioorganic & medicinal chemistry.

[24]  P Boffetta,et al.  Chromosomal aberrations and SCEs as biomarkers of cancer risk. , 2006, Mutation research.

[25]  F. Al-Khodairy,et al.  Evaluation of apoptosis-induction by newly synthesized phthalazine derivatives in breast cancer cell lines. , 2006, Asian Pacific journal of cancer prevention : APJCP.

[26]  E. Akbas,et al.  Synthesis, antibacterial and antifungal activity of some new pyridazinone metal complexes. , 2006, European journal of medicinal chemistry.

[27]  M. P. Mahajan,et al.  PASS assisted search and evaluation of some azetidin-2-ones as C.N.S. active agents. , 2005, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[28]  J. Tözsér,et al.  Beta-lactam compounds as apparently uncompetitive inhibitors of HIV-1 protease. , 2005, Bioorganic & medicinal chemistry letters.

[29]  Sang Woo Park,et al.  Synthesis and cytotoxicity of 1-substituted 2-methyl-1H-imidazo[4,5-g]phthalazine-4,9-dione derivatives. , 2004, Bioorganic & medicinal chemistry.

[30]  D. Doğruer,et al.  Synthesis of New 2‐[1(2H)‐Phthalazinon‐2‐yl]acetamide and 3‐[1(2H)‐Phthalazinon‐2‐yl]propanamide Derivatives as Antinociceptive and Anti‐inflammatory Agents , 2004, Archiv der Pharmazie.

[31]  A. Mathur,et al.  Synthesis of potent and highly selective nonguanidine azetidinone inhibitors of human tryptase. , 2004, Bioorganic & medicinal chemistry letters.

[32]  M. P. Mahajan,et al.  Evaluation of anti-hyperglycemic activity of some novel monocyclic beta lactams. , 2004, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[33]  D. Kuhn,et al.  Novel N-thiolated beta-lactam antibiotics selectively induce apoptosis in human tumor and transformed, but not normal or nontransformed, cells. , 2004, Biochemical Pharmacology.

[34]  A. Karaburun,et al.  Some pyridazinone and phthalazinone derivatives and their vasodilator activities , 2004, Archives of pharmacal research.

[35]  R. Albertini.  Mechanistic insights from biomarker studies: somatic mutations and rodent/human comparisons following exposure to a potential carcinogen. , 2004, IARC scientific publications.

[36]  S. Garbisa,et al.  4-alkylidene-azetidin-2-ones: novel inhibitors of leukocyte elastase and gelatinase. , 2003, Bioorganic & medicinal chemistry.

[37]  M. J. Yunta,et al.  Synthesis and cytotoxic activity of N,N-bis-(3-[N-(4-chlorobenzo[g]-phthalazin-1-yl)]aminopropyl)-N-methylamine: a new potential DNA bisintercalator. , 2003, Bioorganic & medicinal chemistry.

[38]  K. Pihlaja,et al.  1H and 13C NMR Study of 1-Hydrazino-2,3-dihydro-1H-pyrazolo[1,2-a]pyridazine-5,8-diones and -1H-pyrazolo[1,2-b]phthalazine-5,10-diones and Their Ring-Chain Tautomerism , 2002 .

[39]  S. M. Donya.  Cytogenetic studies of some cephalosporines antibiotics on mouse germinal cells , 2002 .

[40]  Y. Aoyama,et al.  Design, synthesis and pharmacological evaluation of 3-benzylazetidine-2-one-based human chymase inhibitors. , 2001, Bioorganic & medicinal chemistry.

[41]  D. Tew,et al.  Lipoprotein-associated PLA2 inhibition--a novel, non-lipid lowering strategy for atherosclerosis therapy. , 2001, Farmaco.

[42]  M. Baraldi,et al.  Synthesis and anticonvulsant activity of novel and potent 6,7-methylenedioxyphthalazin-1(2H)-ones. , 2000, Journal of medicinal chemistry.

[43]  Claudiu T. Supuran,et al.  Carbonic anhydrase inhibitors and their therapeutic potential , 2000 .

[44]  H. Norppa,et al.  Chromosomal aberrations in lymphocytes predict human cancer independently of exposure to carcinogens. European Study Group on Cytogenetic Biomarkers and Health. , 2000, Cancer research.

[45]  Ş. Küçükgüzel,et al.  Synthesis, characterization and antimicrobial evaluation of ethyl 2-arylhydrazono-3-oxobutyrates , 1999 .

[46]  K. Miyazaki,et al.  4-Benzylamino-1-chloro-6-substituted phthalazines: synthesis and inhibitory activity toward phosphodiesterase 5. , 1998, Journal of medicinal chemistry.

[47]  N. Meanwell,et al.  Azetidin-2-one derivatives as inhibitors of thrombin. , 1995, Bioorganic & medicinal chemistry.

[48]  D. Gatehouse,et al.  In vitro and in vivo cytogenetic studies of three beta-lactam antibiotics (penicillin VK, ampicillin and carbenicillin). , 1989, Mutagenesis.

[49]  K. Neftel,et al.  Effects of beta-lactam antibiotics on proliferating eucaryotic cells , 1987, Antimicrobial Agents and Chemotherapy.

[50]  R. Zittoun,et al.  [In vitro inhibition of granulopoiesis by beta-lactam antibiotics. Comparison of piperacillin, mezlocillin, ceftriaxone and ceftazidime]. , 1986, Presse medicale.

[51]  G. Zavarise,et al.  [Evaluation of the effect of cloxacillin on human lymphocyte chromosomes through the study of karyotypic changes and sister chromatid exchanges]. , 1984, Bollettino della Societa italiana di biologia sperimentale.

[52]  Y. Ahuja,et al.  Evaluation of Genotoxicity of Ampicillin and Carbenicillin on Human Lymphocytes in vitro: Chromosome Aberrations, Mitotic Index, Cell Cycle Kinetics, Satellite Associations of Acrocentric Chromosomes and Sister Chromatid Exchanges , 1984, Human toxicology.

[53]  H. Yamada,et al.  Studies of metabolic fate of a new antiallergic agent, azelastine (4-(p-chlorobenzyl)-2-[N-methylperhydroazepinyl-(4)]-1-(2H)-phthalazinone hydrochloride). , 1980, Japanese journal of pharmacology.