- Synthesis and antitumor effects of novel benzyl naphthyl sulfoxide/sulfone derivatives derived from Rigosertib
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In this work, a series of novel benzyl naphthyl sulfoxides/sulfones derived from Rigosertib were designed and synthesized as potential antitumor agents. The in vitro cytotoxicity against four human cancer cell lines (HeLa, MCF-7, HepG2 and SCC-15) and two normal human cell lines (HUVEC and 293T) indicated that some of the sulfones and sulfoxides possessed potent antineoplastic activity that reached nanomolar levels and relatively low toxicity to normal cells. Among them, (2-methoxy-5-((naphthalen-2-ylsulfonyl)methyl)phenyl)glycine (15b) was found to be a promising antitumor drug candidate that could significantly inhibit tumor cell migration and induce tumor cell apoptosis via the p53-Bcl-2-Bax signaling pathway at nanomolar concentrations.
- Tang, Lin,Chen, Tingting,Yang, Hongpeng,Wen, Xiaoxue,Sun, Yunbo,Liu, Shuchen,Peng, Tao,Zhang, Shouguo,Wang, Lin
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p. 37462 - 37471
(2021/12/07)
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- Platinum-Based Modification of Styrylbenzylsulfones as Multifunctional Antitumor Agents: Targeting the RAS/RAF Pathway, Enhancing Antitumor Activity, and Overcoming Multidrug Resistance
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Inhibiting/disturbing the RAS/RAF pathway may benefit the treatment of cancer and overcome the resistance. Utilizing such a pathway as the target, nine styrylbenzylsulfone derivatives generated from the platinum-based modification of the side chain of Rig
- Liu, Zhikun,Wang, Meng,Wang, Hengshan,Fang, Lei,Gou, Shaohua
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p. 186 - 204
(2020/01/22)
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- TYK2 INHIBITORS AND USES THEREOF
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Described herein are compounds that are useful in treating a TYK2-mediated disorder. In some embodiments, the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.
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Paragraph 00253; 00297; 00327
(2020/09/27)
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- INHIBITORS OF INDOLEAMINE 2,3-DIOXYGENASE AND METHODS OF THEIR USE
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The present invention provides compounds of formula (I) wherein all of the variables are as defined herein. These compounds are inhibitors of indoleamine 2,3-dioxygenase (IDO), which may be used as medicaments for the treatment of proliferative disorders, such as cancer, viral infections and/or autoimmune diseases.
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Page/Page column 154
(2020/02/16)
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- Synthesis and Biological Evaluation of 1,2,3-triazole tethered Pyrazoline and Chalcone Derivatives
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A series of pyrazoline derivatives and corresponding chalcone intermediates with substituents same as combretastatin-A4(CA-4) conjugated with triazole nucleus has been synthesized and evaluated for their anticancer potential. Sulphorhodamine B(SRB) assay indicated compound 12c to be the most active compound from the series with GI50 value of 6.7 μm against the human liver carcinoma cell line HepG2. Interestingly, the intermediate 11c exhibited more promising cytotoxicity demonstrating GI50 value of 1.3 μm against the prostate cancer cell line DU145. Compounds 11c and 12c caused accumulation of cells in G2/M phase and inhibited tubulin polymerization. Furthermore, these compounds reduce the mitochondrial membrane potential and activate caspases 3 and 9, thereby indicating their ability to trigger apoptosis.
- Hussaini, Syed Mohammed Ali,Yedla, Poornachandra,Babu, Korrapati Suresh,Shaik, Thokhir B.,Chityal, Ganesh Kumar,Kamal, Ahmed
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- Anti-tubercular agents. Part 8: Synthesis, antibacterial and antitubercular activity of 5-nitrofuran based 1,2,3-triazoles
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A series of 5-nitrofuran-triazole conjugates were synthesized and evaluated for their antimicrobial activity against both Gram-positive and Gram-negative bacterial strains. All the compounds exhibited promising inhibition towards Gram-positive pathogenic strains, while mild inhibitory effects were observed towards Gram-negative bacterial strains. Some of the compounds 8a, 8b, 8e, 8f, 8h are most active among the series exhibiting MIC value of 1.17 μg/ml against different bacterial strains. The bactericidal activity is found to be in accordance with the bacterial growth inhibition data. Compound 8e was found to be equipotent to the standard drug Ciprofloxacin displaying MBC value of 1.17 μg/ml against the bacterial strain Bacillus subtilis. The compounds have also demonstrated promising antibacterial activity against the resistant strain MRSA and were found to be effective inhibitors of biofilm formation. The compound 8b exhibited excellent anti-biofilm activity with IC50 value as low as 0.8 μg/ml. These conjugates were also screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain. Compound 8e showed promising antitubercular activity with MIC value of 0.25 μg/ml. Most of these compounds are less toxic to normal mammalian cells than the widely used antibacterial drug Ciprofloxacin.
- Kamal, Ahmed,Hussaini, Syed Mohammed Ali,Faazil, Shaikh,Poornachandra,Narender Reddy,Kumar, C. Ganesh,Rajput, Vikrant Singh,Rani, Chitra,Sharma, Rashmi,Khan, Inshad Ali,Jagadeesh Babu
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p. 6842 - 6846
(2014/01/06)
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- DERIVATIVES OF 1-PHENYL-2-PYRIDINYL ALKYL ALCOHOLS AS PHOSPHODIESTERASE INHIBITORS
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The invention relates to inhibitors of the phosphodiesterase 4 (PDE4) enzyme. More particularly, the invention relates to compounds that are derivatives of 1-phenyl-2-pyridinyl alkyl alcohols, methods of preparing such compounds, compositions containing them and therapeutic use thereof.
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Paragraph 0618
(2013/04/10)
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- DERIVATIVES OF 1-PHENYL-2-PYRIDINYL ALKYL ALCOHOLS AS PHOSPHODIESTERASE INHIBITORS
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The invention relates to inhibitors of the phosphodiesterase 4 (PDE4) enzyme. More particularly, the invention relates to compounds that are derivatives of 1-phenyl-2-pyridinyl alkyl alcohols, methods of preparing such compounds, compositions containing them and therapeutic use thereof.
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Page/Page column 94
(2013/04/13)
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- Hydrothiolation of benzyl mercaptan to arylacetylene: Application to the synthesis of (E) and (Z)-isomers of on 01910·Na (Rigosertib), a phase III clinical stage anti-cancer agent
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A stereoselective and efficient method for free radical addition of benzyl thiol to aryl acetylene in the presence of Et3B-hexane has been developed for the synthesis of (Z) and (E)-styryl benzyl sulfides where base catalyzed hydrothiolations h
- Pallela, Venkat R.,Mallireddigari, Muralidhar R.,Cosenza, Stephen C.,Akula, Balaiah,Subbaiah, D. R. C. Venkata,Reddy, E. Premkumar,Reddy, M. V. Ramana
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p. 1964 - 1977
(2013/05/22)
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- Discovery of a clinical stage multi-kinase inhibitor sodium (E)-2-{2-methoxy-5-[(2′,4′,6′-trimethoxystyrylsulfonyl)methyl] phenylamino}acetate (ON 01910.Na): Synthesis, structure-activity relationship, and biological activity
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Cyclin D proteins are elevated in many cancer cells, and targeted deletion of cyclin D1 gene in the mammary tissues protects mice from breast cancer. Accordingly, there is an increasing awareness of this novel nonenzymatic target for cancer therapeutics. We have developed novel, nonalkylating styrylbenzylsulfones that induce cell death in wide variety of cancer cells without affecting the proliferation and survival of normal cells. The development of derivatized styrylbenzylsulfones followed logically from a tumor cell cytotoxicity screen performed in our laboratory that did not have an a priori target profile. Modifications of some of the precursor molecules led to lead optimization with regard to tumor cell cytotoxicity. In this report we describe the synthesis and structure-activity relationships of novel, nonalkylating (E)-styrylbenzylsulfones and the development of the novel anticancer agent sodium (E)-2-{2-methoxy-5-[(2′,4′,6′- trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na), which is in phase III trials for myelodysplastic syndromes (MDS) associated with aberrant expression of cyclin D proteins.
- Reddy, M. V. Ramana,Venkatapuram, Padmavathi,Mallireddigari, Muralidhar R.,Pallela, Venkat R.,Cosenza, Stephen C.,Robell, Kimberly A.,Akula, Balaiah,Hoffman, Benjamin S.,Reddy, E. Premkumar
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p. 6254 - 6276
(2011/11/01)
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- COMPOSITION AND METHODS FOR THE TREATMENT OF MYELODYSPLASTIC SYNDROME AND ACUTE MYELOID LEUKEMIA
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Methods and compositions are provided for treating myelodysplastic syndrome and acute myeloid leukemia, wherein the composition comprises at least one compound according to Formula I: wherein R1 is selected from the group consisting of —NH2, —NH—CH2—CO2H, —NH—CH(CH3)—CO2H, and —NH—C(CH3)2—CO2H, or a pharmaceutically acceptable salt of such a compound; and a DNA methyltransferase inhibitor, or a pharmaceutically acceptable salt thereof.
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- COMPOSITION AND METHODS FOR THE TREATMENT OF MYELODYSPLASTIC SYNDROME AND ACUTE MYELOID LEUKEMIA
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Methods and compositions are provided for treating myelodysplastic syndrome and acute myeloid leukemia, wherein the composition comprises at least one compound according to Formula I: (I) wherein R1 is selected from the group consisting of -NH2, -NH-CH2-CO2H, -NH-CH(CH3)-CO2H, and -NH-C(CH3)2-CO2H, or a pharmaceutically acceptable salt of such a compound; and a DNA methyltransferase inhibitor, or a pharmaceutically acceptable salt thereof.
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Page/Page column 30
(2008/06/13)
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- ACTIVATED CYTOTOXIC COMPOUNDS FOR ATTACHMENT TO TARGETING MOLECULES FOR THE TREATMENT OF MAMMALIAN DISEASE CONDITIONS
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Activated cytotoxic compounds are described for attachment to targeting molecules for the treatment of a mammalian disease condition which comprise, an activator, a spacer linker, a linker (e.g., self-immolative), and a cytotoxic drug selected from the group consisting of AMINO-SUBSTITUTED (E)-2,6-DIALKOXYSTYRYL 4-SUBSTITUTED BENZYLSULFONES, AMINO-AND- HYDROXY SUBSTITUTED STYRYLSULFONANILIDES, and SUBSTITUTED PHENOXY- AND PHENYLTHIO-STYRYLSULFONE DERIVATIVES. Activated cytotoxic compound attached to a targeting molecule are described wherein the targeting molecule is selected from the group consisting essentially of an antibody, a receptor, a ligand, a cytokine, a hormone, and a signal transduction molecule. The invention is further directed to a method of treatment of disease conditions.
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Page/Page column 52-53
(2010/11/30)
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- A convenient method for the preparation of benzyl isocyanides
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Treatment of benzyl halides with silver salts (AgClO4, AgBF 4, or AgOTf) and trimethylsilyl cyanide (TMSCN) in CH 2Cl2 followed by cleavage of the carbon-silicon bond with aqueous NaHCO3 or TBAF directly afforded the corresponding isocyanides. Georg Thieme Verlag Stuttgart.
- Kitano, Yoshikazu,Manoda, Tetsuya,Miura, Teppei,Chiba, Kazuhiro,Tada, Masahiro
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p. 405 - 410
(2007/10/03)
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- COMPOSITION AND METHODS FOR THE TREATMENT OF PROLIFERATIVE DISEASES
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Methods and compositions are provided for treating proliferative disorders, wherein the composition comprises at least one compound according to Formula (I), wherein R1 is selected from the group consisting of -OH, -NH2, -NH-CH2
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Page/Page column 32
(2010/11/24)
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- Design, synthesis, and biological evaluation of combretastatin nitrogen-containing derivatives as inhibitors of tubulin assembly and vascular disrupting agents
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A series of analogs with nitro or serinamide substituents at the C-2′-, C-5′-, or C-6′-position of the combretastatin A-4 (CA4) B-ring was synthesized and evaluated for cytotoxic effects against heart endothelioma cells, blood flow reduction to tumors in
- Monk, Keith A.,Siles, Rogelio,Hadimani, Mallinath B.,Mugabe, Benon E.,Ackley, J. Freeland,Studerus, Scott W.,Edvardsen, Klaus,Trawick, Mary Lynn,Garner, Charles M.,Rhodes, Monte R.,Pettit, George R.,Pinney, Kevin G.
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p. 3231 - 3244
(2007/10/03)
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- Method for preparing Combretastatin
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The invention concerns novel methods for preparing Combretastatin by Wittig condensation between nitromethoxy-benzaldehyde and a trimethoxybenzyl phosphonium salt or inversely a nitromethoxybenzyl phosphonium salt with trimethoxybenzylaldehyde or further by a Wittig reaction on the same derivatives whereof the nitro function has been reduced into an amino group.
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Page/Page column 9-10
(2008/06/13)
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- Imidazopyridinone derivatives and their use as phosphodiesterase inhibitors
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A compound (Ia): wherein the variables are defined in the specification, its prodrug or a pharmaceutically acceptable salt thereof useful in the treatment of angina, hypertension etc.
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- Substituted phenylpropionic acid derivatives
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The invention provides novel substituted phenylpropionic acid derivatives that bind to the receptor as ligands of human peroxisome proliferator-activated receptor a (PPARα) to activate and exhibit potent lipid-decreasing action, and processes for preparin
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- Synthesis and biological evaluation of aryl azide derivatives of combretastatin a-4 as molecular probes for tubulin
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Two new aryl azides, (Z)-1-(3'-azido-4'-methoxyphenyl)-2-(3'',4'',5''-trimethoxyphenyl)ethene 9 and (Z)-1-(4'-azido-3'-methoxyphenyl)-2-(3'',4'',5''-trimethoxyphenyl)ethene 5, modeled after the potent antitumor, antimitotic agent combretastatin A-4 (CA-4)
- Pinney, Kevin G.,Mejia, Maria P.,Villalobos, Victor M.,Rosenquist, Brent E.,Pettit, George R.,Verdier-Pinard, Pascal,Hamel, Ernest
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p. 2417 - 2425
(2007/10/03)
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- Convenient synthesis of phidolopin and analogs and their biological activities
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A convenient synthesis of phidolopin (7), a marine natural product, 8-bromophidolopin (14) and other analogs (13) has been reported. Antibacterial (in vitro), antifungal (in vitro) and antiallergic (% PCA inhibition, in vivo) activities of compounds 7, 13 and 14 are also reported.
- Avasthi,Chandra,Rawat,Bhakuni
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p. 437 - 440
(2007/10/03)
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