Pyridazines I

The terminal step of ligation of single and/or double-strand breaks during physiological processes such as DNA replication, repair and recombination requires participation of DNA ligases in all mammals. DNA Ligase I has been well characterised to play vital roles during these processes. Considering the indispensable role of DNA Ligase I, a therapeutic strategy to impede proliferation of cancer cells is by using specific small molecule inhibitors against it. In the present study, we have designed and chemically synthesised putative DNA Ligase I inhibitors. Based on various biochemical and biophysical screening approaches, we identify two prospective DNA Ligase I inhibitors, SCR17 and SCR21. Both the inhibitors blocked ligation of nicks on DNA in a concentration-dependent manner, when catalysed by cell-free extracts or purified Ligase I. Docking studies in conjunction with biolayer interferometry and gel shift assays revealed that both SCR17 and SCR21 can bind to Ligase I, particularly to the DNA Binding Domain of Ligase I with KD values in nanomolar range. The inhibitors did not show significant affinity towards DNA Ligase III and DNA Ligase IV. Further, addition of Ligase I could restore the joining, when the inhibitors were treated with testicular cell-free extracts. Ex vivo studies using multiple assays showed that even though cell death was limited in the presence of inhibitors in cancer cells, their proliferation was compromised. Hence, we identify two promising DNA Ligase I inhibitors, which can be used in biochemical and cellular assays, and could be further modified and optimised to target cancer cells. © 2016 Wiley Periodicals, Inc.

show abstract

“…Recrystallize the product 2 (Scheme ) from water to get pale yellow needle. Yield‐ 80%; MP‐193–195°C (Lit 195°C) .…”

Section: Methodsmentioning

confidence: 99%

Identification and characterization of novel ligase I inhibitors

Pandey

Kumar

Goldsmith

et al. 2016

Molecular Carcinogenesis

View full text Add to dashboard Cite

show abstract

“…It is known [11] that the reaction of I with 95% hydrazine in methanol yields exclusively 4-hydrazino-5-chloro-6-pyridazone X. Its structure was determined by hydrogenation (Pd/C) and independent synthesis of the dechlorination products.…”

mentioning

confidence: 99%

“…In the pyridazine series, available substrates for nucleophilic substitution are 4,5-dichloro-6-pyridazone I, 1-methyl-4, 5-dichloro-6-pyridazone II, 3, 4, 5-trichloropyridazine III, 3,6-dichloropyridazine IV, and 3-methyl-6-chloropyridazine V [538]: It is known that pyridazone I reacts with ammonia [9], alkylamines [10], and hydrazine [11] selectively with chlorine substitution at the 4-position of the pyridazine ring. This is due to the activating effect of the keto group on the 4-position in I [10,12].…”

mentioning

confidence: 99%

Nucleophilic substitution of chlorine with hydrazine and methylhydrazine in chlorinated pyridazines and pyridazones

Baranov¹,

Tsypin²,

Laskin³

2004

Russ J Appl Chem

View full text Add to dashboard Cite

The reactions of methylhydrazine and hydrazine hydrate with chlorinated pyridazines and pyridazones were studied.The reactivity of hydrazine and methylhydrazine toward aliphatic and aromatic compounds has been well studied [1,2]. However, data on reactions of hydrazine and methylhydrazine with heterocycles and, in particular, with pyridazines are scarce. The interest in the chemistry of hydrazine is determined by its diverse applications in science and technology. In particular, hydrazine derivatives are widely used in medicine as physiologically active compounds exhibiting antitubercular, anticancer, radiation-protective, and other effects; in agriculture, as plant growth regulators and stimulants, as insecticides, fungicides, and hebricides; and in industry, for preparing synthetic fibers, films, and coatings [3,4].In this study we examined the reactions of hydrazine hydrate and methylhydrazine with some chlorinated pyridazines and pyridazones.In the pyridazine series, available substrates for nucleophilic substitution are 4,5-dichloro-6-pyridazone I, 1-methyl-4, 5-dichloro-6-pyridazone II, 3, 4, 5-trichloropyridazine III, 3,6-dichloropyridazine IV, and 3-methyl-6-chloropyridazine V [538]: Q 8 ? C 9 9 O N N Q R S Cl Cl Q S Cl Cl 9 Cl 6 N N 9 Cl 6 N N 9 R I, II III IV, V Q 8 ? C 9 9 O N N Q R S Cl Cl Q S Cl Cl 9 Cl 6 N N 9 Cl 6 N N 9 R I, II III IV, V where R = H (I), Me (II, V), Cl (IV).It is known that pyridazone I reacts with ammonia [9], alkylamines [10], and hydrazine [11] selectively with chlorine substitution at the 4-position of the pyridazine ring. This is due to the activating effect of the keto group on the 4-position in I [10,12]. However, it has been reported [13,14] that the reaction of I with ammonia yields a mixture of 4-amino-5-chloro-6-pyridazone VI and 5-amino-4-chloro-6-pyridazone VII.Our experiments showed that pyridazone I reacts with methylhydrazine in 2-propanol strictly specifically to give 4-(1-methylhydrazino)-5-chloro-6-pyridazone VIII in 95% yield. In methylation of VIII with dimethyl sulfate in methanol in the presence of sodium, the reaction occurs selectively at the 1-position of the pyridazine ring, giving 1-methyl-4-(1-methylhydrazino)-5-chloro-6-pyridazone IX in 37% yield.It is known [11] that the reaction of I with 95% hydrazine in methanol yields exclusively 4-hydrazino-5-chloro-6-pyridazone X. Its structure was determined by hydrogenation (Pd/C) and independent synthesis of the dechlorination products. However, under the experimental conditions, the reaction of I with 100% hydrazine hydrate in ethanol yields a mixture of pyridazone X and 5-hydrazino-4-chloro-6-pyridazone XI in 29 and 48% yields, respectively, which is confirmed by the 1 H NMR and TLC data, and also by depression of the melting point, observed on mixing X and XI.Then we performed methylation of X with dimethyl sulfate. The reaction was performed in the system 10% aqueous NaOH solution3CHCl 3 in the presence of Et 4 NI. The reaction occurs selectively at the N 1 atom of the hydrazine moiety, yielding pyridazon...

show abstract

The Pyridazinones, Alkoxy‐ and Aryloxy‐Pyridazines, and Related Compounds

Mason¹,

Aldous

1973

Chemistry of Heterocyclic Compounds: A Series of Monographs

View full text Add to dashboard Cite

Pyridazines I

Cited by 17 publications

References 7 publications

Identification and characterization of novel ligase I inhibitors

Identification and characterization of novel ligase I inhibitors

Nucleophilic substitution of chlorine with hydrazine and methylhydrazine in chlorinated pyridazines and pyridazones

The Pyridazinones, Alkoxy‐ and Aryloxy‐Pyridazines, and Related Compounds

Contact Info

Product

Resources

About