Design,synthesis and evaluation of 2-phenylisothiazolidin-3-one-1,1-dioxides as a new class of human protein kinase CK2 inhibitors

Abstract

The synthesis and in vitro evaluation of 40 new 2-phenylisothiazolidin-3-one-1,1-dioxide derivatives are described. The optimization based on biological screening data and molecular modeling resulted in a 10-fold increase in inhibitory activity compared with previously reported inhibitors of this class and led to the identification of 3-{[2-chloro-4-(1,1-dioxido-3-oxoisothiazolidin-2-yl)benzoyl]amino}benzoic acid, a potent inhibitor of human protein kinase CK2 (?C₅₀?=?1.5?μM).     

Structure-based design of protein tyrosine phosphatase-1B inhibitors

Using structure-based design, a new class of inhibitors of protein tyrosine phosphatase-1B (PTP1B) has been identified, which incorporate the 1,2,5-thiadiazolidin-3-one-1,1-dioxide template.     

Synthesis, cytotoxic activity, NMR study and stereochemical effects of some new pyrano[3,2-b]thioxanthen-6-ones and pyrano[2,3-c]thioxanthen-7-ones

Some new substituted pyrano[3,2-b]thioxanthen-6-ones and pyrano[2,3-c]thioxanthen-7-ones were prepared and their cytotoxic activity was evaluated using acronycine as the reference compound. The conformation of the molecules was also investigated in an effort to correlate this parameter with the biological activity.     

Antimicrobial activity of quinoxaline 1,4-dioxide with 2- and 3-substituted derivatives

Quinoxaline is a chemical compound that presents a structure that is similar to quinolone antibiotics. The present work reports the study of the antimicrobial activity of quinoxaline N,N-dioxide and some derivatives against bacterial and yeast strains. The compounds studied were quinoxaline-1,4-dioxide (QNX), 2-methylquinoxaline-1,4-dioxide (2MQNX), 2-methyl-3-benzoylquinoxaline-1,4-dioxide (2M3BenzoylQNX), 2-methyl-3-benzylquinoxaline-1,4-dioxide (2M3BQNX), 2-amino-3-cyanoquinoxaline-1,4-dioxide (2A3CQNX), 3-methyl-2-quinoxalinecarboxamide-1,4-dioxide (3M2QNXC), 2-hydroxyphenazine-N,N-dioxide (2HF) and 3-methyl-N-(2-methylphenyl)quinoxalinecarboxamide-1,4-dioxide (3MN(2MF)QNXC). The prokaryotic strains used were Staphylococcus aureus ATCC 6538, S. aureus ATCC 6538P, S. aureus ATCC 29213, Escherichia coli ATCC 25922, E. coli S3R9, E. coli S3R22, E. coli TEM-1 CTX-M9, E. coli TEM-1, E. coli AmpC Mox-2, E. coli CTX-M2 e E. coli CTX-M9. The Candida albicans ATCC 10231 and Saccharomyces cerevisiae PYCC 4072 were used as eukaryotic strains. For the compounds that presented activity using the disk diffusion method, the minimum inhibitory concentration (MIC) was determined. The alterations of cellular viability were evaluated in a time-course assay. Death curves for bacteria and growth curves for S. cerevisiae PYCC 4072 were also accessed. The results obtained suggest potential new drugs for antimicrobial activity chemotherapy since the MIC's determined present low values and cellular viability tests show the complete elimination of the bacterial strain. Also, the cellular viability tests for the eukaryotic model, S. cerevisiae, indicate low toxicity for the compounds tested.     

Probing acid replacements of thiophene PTP1B inhibitors

The following account describes our systematic effort to replace one of the carboxylate groups of our diacid thiophene PTP1B inhibitors. Active hits were validated using enzymatic assays before pursuing efforts to improve the potency. Only when the C2 carboxylic acid was replaced with another ionizable functional group was reversible and competitive inhibition retained. Use of a tetrazole ring or 1,2,5-thiadiazolidine-3-one-1,1-dioxide as a carboxylate mimetic led to the discovery of two unique starting series that showed improved permeability (PAMPA) and potency of the order of 300nM. The SAR from these efforts underscores some of the major challenges in developing small molecule inhibitors for PTP1B.     

Cyclic voltammetry of phenazines and quinoxalines including mono- and di-N-oxides. Relation to structure and antimicrobial activity

Cyclic voltammetry data were obtained for eight phenazines and phenazine-N-oxides, and eleven quinoxalines and quinoxaline-N-oxides: 1,6-phenazine-diol-5,10-dioxide (iodinin), iodinin copper complex, 6-methoxy-1-phenazinol-5,10-dioxide 1,6-dimethoxyphenazine-5-oxide, 1,6-phenazinediol, 1,6-dimethoxyphenazine, quinoxaline-1,4-dioxide, 2-methylquinoxaline-1,4-dioxide, 2,3-diphenylquinoxaline-1,4-dioxide, 2-carboxyquinoxaline-1,4-dioxide, 5-hydroxyquinoxaline-1,4-dioxide, 5-hydroxy-8-methoxyquinoxaline-1,4-dioxide, 2-methylquinoxaline, 2,3-diphenylquinoxaline, 5-hydroxyquinoxaline, 5-hydroxy-8-methoxyquinoxaline and 2-(2-quinoxalinylmethylene)hydrazine carboxylic acid methyl ester-1,4-dioxide (Carbadox). The di-N-oxides exhibit the most positive E1/2 values within each class. Reversible first wave reductions were observed for iodinin, iodinin copper complex, 1,6-dimethoxyphenazine-5-oxide, 1,6-dimethoxyphenazine, quinoxaline-1,4-dioxide, 2-methylquinoxaline-1,4-oxide and 2,3-diphenylquinoxaline-1,4-dioxide. The results are correlated with structure. Some relationships exist between reduction potential and reported antimicrobial activity. A possible mechanism of drug action is addressed.     

Secondary metabolites from Opuntia ficus-indica var. saboten

A butanol fraction, from the methanolic extract of Opuntia ficus-indica var. saboten, on purification either by preparative TLC or reversed phase HPLC, yielded three chemical components: isorhamnetin 3-O-(6'-O-E-feruloyl)neohesperidoside (1), (6R)-9,10-dihydroxy-4,7-megastigmadien-3-one-9-O-beta-D-glucopyranoside (2) and (6S)-9,10-dihydroxy-4,7-megastigmadien-3-one-9-O-beta-D-glucopyranoside (3) along with 15 known compounds. Structures of compounds (1-3) were elucidated by aid of spectroscopic analyses. The absolute stereochemistry in compounds 2 and 3 was established with the help of CD data analysis and comparison with the literature data. In a DPPH radical scavenging assay, compound 1 showed moderate inhibitory activity (IC50 = 45.58 microg/ml).     

中国南海侧扁软柳珊瑚中孕甾烷类化学成分的研究(英文)

从南海侧扁软柳珊瑚Subergorgia suberosa的二氯甲烷-甲醇提取物中首次分离鉴定了8个孕甾烷类化合物,经波谱鉴定为3β-O-palmitoyl-pregn-5-ene-20-one-3-ol (1),3β-O-palmitoyl-5α-pregn-20-one-3-ol (2),5α-pregn-1-ene-3,20-dione (3),3β,5α-pregn-20-one-3-ol (4),3β-pregn-5-ene-20-one-3-ol (5),3β,5β-pregn-20-one-3-ol (6),5β-pregn-3,20-dione (7),pregn-4-ene-3,20-dione (8).其中化合物1,2为新化合物.     

The degradation of beta-sitosterol by Pseudomonas sp. NCIB 10590 under aerobic conditions

The bacterial degradation of beta-sitosterol by Pseudomonas sp NCIB 10590 has been studied. Major biotransformation products included 24-ethylcholest-4-en-3-one, androsta-1,4-diene-3,17-dione, 3-oxochol-4-en-3-one-24-oic acid and 3-oxopregn-4-en-3-one-20-carboxylic acid. Minor products identified were 26-hydroxy-24-ethylcholest-4-en-3-one, androst-4-ene-3,17-dione, 3-oxo-24-ethylcholest-4-en-26-oic acid, 3-oxochola-1,4-dien-3-one-24-oic acid, 3-oxopregna-1,4-dien-3-one-20 carboxylic acid and 9 alpha-hydroxyandrosta-1,4-diene-3,17-dione. Studies with selected inhibitors have enabled the elucidation of a comprehensive pathway of beta-sitosterol degradation by bacteria.     

DNA strand cleaving properties and hypoxia-selective cytotoxicity of 7-chloro-2-thienylcarbonyl-3-trifluoromethylquinoxaline 1,4-dioxide

The heterocyclic N-oxide, 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, 1), shows promising antitumor activity in preclinical studies, but there is a continuing need to explore new compounds in this general structural category. In the work described here, we examined the properties of 7-chloro-2-thienylcarbonyl-3-trifluoromethylquinoxaline 1,4-dioxide (9h). We find that 9h causes redox-activated, hypoxia-selective DNA cleavage that mirrors the lead compound, tirapazamine, in both mechanism and potency. Furthermore, we find that 9h displays hypoxia-selective cytotoxicity against human cancer cell lines.     

Redox-activated, hypoxia-selective DNA cleavage by quinoxaline 1,4-di-N-oxide.

Quinoxaline 1,4-dioxide (4) is the historical prototype for modern heterocyclic N-oxide antitumor agents such as 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, 1) and 3-amino-2-quinoxalinecarbonitrile 1,4-dioxide (11). Early experiments in bacterial cell lines suggested that enzymatic, single-electron reduction of quinoxaline 1,4-dioxides under low-oxygen (hypoxic) conditions leads to DNA damage. Here the ability of quinoxaline 1,4-dioxide to cleave DNA has been explicitly characterized using in vitro assays. The hypoxia-selective DNA-cleaving properties of 4 reported here may provide a chemical basis for understanding the cytotoxic and mutagenic activities of various quinoxaline 1,4-dioxide antibiotics.     

Bianthraquinones from Cassia siamea

The isolation of two bianthraquinones, 1,1',3,8,8'-pentahydroxy-3',6-dimethyl[2,2'-bianthracene]-9,9',10,10'-tetrone and 7-chloro-1,1',6,8,8'-pentahydroxy-3,3'-dimethyl[2,2'-bianthracene]-9,9',10,10'-tetrone, from the root bark of Cassia siamea is reported. The structures were established by analysis of spectroscopic data and 7-chloro-1,1',6,8,8'-pentahydroxy-3,3'-dimethyl[2,2'-bianthracene]-9,9',10,10'-tetrone was determined on the direct comparison with synthetic compound.     

Synthesis and anticonvulsant activity of bioisosteres of trimethadione,N-derivative-1,2,3-oxathiazolidine-4-one-2,2-dioxides from α-hydroxyamides

The synthesis and anticonvulsant activity of novel heterocycles N-derivative-1,2,3-oxathiazolidine-4-one-2,2-dioxides, bioisosteres of trimethadione (TMD, oxazolidine-2,4-dione) and phenytoin (PHE), are described. TMD is an anticonvulsant drug widely used against absences seizures in the early 80’s and PHE is an antiepileptic drug with a wide spectrum activity. The intermediates of synthesis of N-derivative-1,2,3-oxathiazolidine-4-one-2,2-dioxides, α-hydroxyamides, were obtained using microwave assisted synthesis. Anticonvulsant screening was performed in mice after intraperitoneal administration in the maximal electroshock seizure test (MES) and subcutaneous pentylenetetrazole seizures test (scPTZ). These new compounds showed a wide spectrum activity and were no neurotoxic in the RotoRod test. α-Hydroxyamides and N-derivative-1,2,3-oxathiazolidine-4-one-2,2-dioxides were 3–4700 times more potent than valproic acid in the MES test. Quantification of anticonvulsant protection was calculated (ED₅₀) for the most active candidates; α-hydroxyamides 3a–c and 3e, and N-derivative-oxathiazolidine-4-one-2,2-dioxides 5a–c with ED₅₀ values of 9.1, 53.9, 44.6, 25.2, 15.1, 91.1 and 0.06 mg/kg, respectively, in the MES test.     

Guggullipid derivatives: synthesis and applications

Two guggullipid derivatives, Z-guggulsulfate [4,17(20)-pregnadiene-3-one-16β-sulfate] sodium salt and Z-guggullaurate [4,17(20)-pregnadiene-3-one-16β-laurate], have been synthesized and evaluated for liposomal drug delivery system. Its precursor, Z-guggulsterol [4,17(20)-pregnadiene-3-one-16β-ol], is also synthesized in gram scale starting from guggulsterone using the novel combination of known reactions in fewer steps and with higher yield than previously reported synthesis. These new synthetic guggullipid derivatives were also used in the preparation of liposomes. This new class of lipid molecules will be a useful tool in the development of nanosomal or liposomal drug delivery system.     

Study on the mutagenicity of nifurtimox and eight derivatives with the L-arabinose resistance test of Salmonella typhimurium

The mutagenicity of nifurtimox (nfx) and 8 nfx analogues has been investigated with the L-arabinose forward-mutation assay of Salmonella typhimurium. The nfx analogues tested were obtained by replacing the 3-methyl-4-yl-tetrahydro-1,4-thiazine-1,1-dioxide group of the parent compound with the following other groups: indazol-1-yl (1); pyrazol-1-yl (2); benzimidazol-1-yl (3); 1,2,4-triazol-4-yl (4); 1-methyl-3-methylthio-1,2,4-triazol-4-yl-5-thione (5); 3,5-bis(methylthio)-1,2,4-triazol-4-yl (6); 1-adamantyl (7); 4,6-diphenylpyridin-1-yl-2-one (8). The mutagenic activity of each chemical was determined by the standard plate-incorporation test, in the presence or absence of the S9 activation mixture. The 9 compounds were mutagenic and exhibited linear dose-mutagenic response relationships. They were direct-acting mutagens and showed a nearly 1000-fold range in mutagenic potency from chemical 1 to nfx. In most cases, the addition of S9 mixture to the test plates decreased the mutagenicity of compounds. This effect was particularly noticeable in the case of chemicals 1-3, 5 and 7 where a more than 70% decrease in mutagenic activity was observed in the presence of the S9 mixture. The mutagenic potency of compounds in the Ara test showed a negative linear correlation with previously reported antitrypanosomal activity. Thus, chemicals 6 and 8 with in vitro activities against Trypanosoma cruzi clearly superior to that of nfx showed 2 of the lowest mutagenic potencies in the Ara test and these were only somewhat higher than the mutagenicity of the reference drug.     

Inhibition of adenosine-3',5'-cyclic monophosphate phosphodiesterase by potential antiallergic compounds.

The potential antiallergic compounds doxantrazole (3- (5-tetrazolyl)-thioxanthone 10, 10-dioxide) and CTD (3- carboxythioxanthone 10, 10-dioxide) are inhibitors of the phosphodiesterases of human and guinea pig lung and beef heart. Disodium cromoglycate is a weak inhibitor of all these enzymes. It is suggested that the antiallergic activity of doxantrazole and CTD is due, at least in part, to their ability to elevate intracellular cAMP levels by inhibiting phosphodiesterase activity.     

Synthesis and bioactivity of 4,10-dimethyl-pyridino[2,3-h]quinolin-2(1H)-one-9-carboxylic acid and its esters

4,10-Dimethyl-pyridino[2,3-h]quinolin-2(1H)-one-9-carboxylic acid (1) was synthesized by a new approach via the key intermediate 7-[1-aza-2-(dimethylamino)vinyl]-4-methylquinolin-2(1H)-one (4). Compound 1 and its esters were evaluated in cytotoxicity and anti-HIV assays. The 9-carboxyl (1s)-endo-(-)-borneol ester (9) showed marginal cytotoxic activity in CAK1-1, HOS, KB, and HCT-8 cells.     

Cytotoxic cholestane and pregnane glycosides from Tribulus macropterus

The methanol extract of the whole parts of Tribulus macropterus Boiss. (family Zygophyllaceae) showed cytotoxic activity against a human tumour cell line (hepatocyte generation 2, HepG2) (IC50 = 2.9 microg/ml). The n-butanolic fraction obtained from successive fractionation of the methanolic extract exhibited activity against HepG2 (IC50 = 2.6 microg/ml). Therefore, this fraction was subjected to separation using different chromatographic techniques. Five compounds, 1-5, were isolated and identified as: (22S,25S)-16beta,22,26-trihydroxy-cholest-4-en-3-one-16-O-beta-D-glucopyranosyl-(1-->3)-beta-D-xylopyranoside (1), (22S,25S)-16beta,22,26-trihydroxy-cholest-4-en-3-one-16-O-beta-D-glucopyranosyl-(1-->3)-beta-D-glucopyranoside (2), sucrose (3), D-pinitol (4) and 3beta-hydroxy-5a-pregn-16(17)en-20-one-3-O-beta-D-xylopyranosyl-(1-->2)-[beta-D-xylopyranosyl-(1-->3)]-beta-D-glucopyranosyl-(1-->4)-[alpha-L-rhamnopyranosyl-(1-->2)]-beta-D-ga-lactopyranoside (5) on the basis of spectroscopic and chemical data. The three steroidal compounds 1, 2 and 5 were also tested against the same cell line HepG2 and their IC50 values were 2.4, 2.2 and 1.1 microg/ml, respectively.     

Biaryls and heterobiaryls as alpha-glucosidase and protein tyrosine phosphatase inhibitors

Various 6-aryl-4-substituted-2H-pyran-2-one-3-carbonitriles (1a-d) have been synthesized as precursor for the synthesis of 3,4-dihydro-1H-isothiochroman (2a) and benzocycloalkanes (2b-e). Highly functionalized 9-thiaphenanthrene (3b) and phenanthrene (3a) have also been obtained from the reaction of 1c with thiochroman-4-one and 1-tetralone separately. Similarly 4 has been obtained by the ring transformation of 1d by 4-trifluoromethylacetophenone. Most of the synthesized compounds were evaluated for alpha-glucosidase and protein tyrosine phosphatase inhibitory activities. Some of the compounds, 2a, 3a and b and 4 displayed better alpha-glucosidase inhibitory activity compared to standard drug acarbose.