- Anthranilamide-based 2-phenylcyclopropane-1-carboxamides, 1,1'-biphenyl-4-carboxamides and 1,1'-biphenyl-2-carboxamides: Synthesis biological evaluation and mechanism of action
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Several anthranilamide-based 2-phenylcyclopropane-1-carboxamides 13a-f, 1,1’-biphenyl-4-carboxamides 14a-f and 1,1’-biphenyl-2-carboxamides 17a-f were obtained by a multistep procedure starting from the (1S,2S)-2-phenylcyclopropane-1-carbonyl chloride 11, the 1,1'-biphenyl-4-carbonyl chloride 12 or the 1,1'-biphenyl-2-carbonyl chloride 16 with the appropriate anthranilamide derivative 10a-f. Derivatives 13a-f, 14a-f and 17a-f showed antiproliferative activity against human leukemia K562?cells. Among these derivatives 13b, 14b and 17b exerted a particular cytotoxic effect on tumor cells. Derivative 17b showed a better antitumoral effect on K562?cells than 13b and 14b. Analyses performed to explore 17b mode of action revealed that it induced an arrest in G2/M phase of cell cycle which was consequent to DNA lesions as demonstrated by the increase in phospho-ATM and γH2AX, two known markers of DNA repair response system. The effect of 17b was also related to ROS generation, activation of JNK and induction of caspase-3 dependent apoptosis.
- Raffa, Demetrio,Plescia, Fabiana,Maggio, Benedetta,Raimondi, Maria Valeria,D'Anneo, Antonella,Lauricella, Marianna,Daidone, Giuseppe
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p. 262 - 273
(2017/04/03)
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- Copper-Catalyzed One-pot Synthesis of Pyrimidines from Amides, N,N′-dimethylformamide dimethylacetal, and Enamines
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A versatile copper catalyzed one-pot synthesis of diversely substituted pyrimidines directly from amides, N,N′-dimethylformamide dimethylacetal (DMF?DMA) and enamines has been established. The reaction involved the two C?N bonds and one C?C bond formation by formal [2+1+3] annulation approach to pyrimidines. This protocol is based on the use of readily available primary amides, DMF?DMA and enamines to install di- and tri-substituted pyrimidine structure with diverse functionality in one-pot manner, which makes this strategy to be appealing for the medicinal chemistry. (Figure presented.).
- Jalani, Hitesh B.,Cai, Wangshui,Lu, Hongjian
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supporting information
p. 2509 - 2513
(2017/07/22)
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- Synthesis, antiproliferative activity and possible mechanism of action of novel 2-acetamidobenzamides bearing the 2-phenoxy functionality
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Several new 2-(2-phenoxyacetamido)benzamides 17a-v, 21 and 22 were synthesized by stirring in pyridine the acid chlorides 16a-e and the appropriate5-R-4-R1-2-aminobenzamide 15a-e and initially evaluated in vitro for antiproliferative activity against the K562 (human chronic myelogenous leukemia) cell line. Some of synthesized compounds were evaluated for their in vitro antiproliferative activity against the full NCI tumor cell line panel derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). The most active compounds caused an arrest of K562 cells in the G0-G1 phase of cell cycle and induction of apoptosis, which was mediated by caspase activation.
- Raffa, Demetrio,Maggio, Benedetta,Plescia, Fabiana,Cascioferro, Stella,Raimondi, Maria Valeria,Cancemi, Gabriella,D'Anneo, Antonella,Lauricella, Marianna,Cusimano, Maria Grazia,Bai, Ruoli,Hamel, Ernest,Daidone, Giuseppe
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p. 6305 - 6316
(2015/10/05)
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- 2-Cinnamamido, 2-(3-phenylpropiolamido), and 2-(3-phenylpropanamido) benzamides: Synthesis, antiproliferativeactivity, and mechanism of action
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Several new benzamides 4a-q were synthesized by stirring in pyridine the acid chlorides 3a-q with the appropriate anthranilamide derivatives 2a-g. Some of the synthesized compounds were evaluated for their in vitro antiproliferative activity against a panel of 5 human cell lines (K562 human chronic myelogenous leukemia cells, MCF-7 breast cancer cells, HTC-116 and HT26 colon cancer cells and NCI H460 non-small cell lung cancer cells).
- Raffa, Demetrio,Maggio, Benedetta,Raimondi, Maria Valeria,Cusimano, Maria Grazia,Amico, Giandomenico,Carollo, Anna,Conaldi, Pier Giulio,Bai, Ruoli,Hamel, Ernest,Daidone, Giuseppe
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p. 427 - 435
(2013/10/01)
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- Design and synthesis of 6,7-dimethoxyquinazoline analogs as multi-targeted ligands for α1- and AII-receptors antagonism
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Multiple-targeted ligands can have certain advantages for the management of hypertension which has multiple controls. Molecules with dual bioactivities are available in literature for treating metabolic disorders like diabetes, hypertension and hypercholesterolemia. After scrutinizing the SAR of prazosin-type α1-blockers and AII-antagonists it was planned to develop dual α1- and AII-antagonists. Five series of quinazoline derivatives were synthesized and evaluated as dual α1- and AII-antagonists on rat aortic strips for the blockade of known α1- and AII-agonist mediated contractions. Many compounds showed balanced activity on both the receptors but compound (22) was found to be the most active derivative having higher antagonistic activity on both the receptors. In the in vivo experiments the chosen compound (22) was slightly less active than prazosin but was found to be equipotent to losartan. These findings shed a new light on the structural requirements for both α1- as well as AII-receptor antagonists.
- Yadav,Naik,Gandhi,Chauhan,Giridhar
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p. 3959 - 3966
(2013/07/27)
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- RHO KINASE INHIBITORS
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The present invention relates to inhibitors of ROCK1 and ROCK2, which may be selective for ROCK2, and methods of modulating the pharmacokinetic and/or pharmacodynamic properties of such compounds. Also provided are methods of inhibiting ROCK1 and/or ROCK2. Also provided are treatments combining inhibitors of ROCK1 and/or ROCK2 with statins.
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Page/Page column 149
(2010/10/03)
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- RHO KINASE INHIBITORS
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The present invention relates to inhibitors of ROCKl and R0CK2, which may be selective for R0CK2, and methods of modulating the pharmacokinetic and/or pharmacodynamic properties of such compounds. Also provided are methods of inhibiting ROCKl and/or R0CK2. Also provided are treatments combining inhibitors of ROCKl and/or R0CK2 with statins.
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Page/Page column 153
(2008/12/05)
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- QUINAZOLINE DERIVATIVE USEFUL AS TOLL-LIKE RECEPTOR ANTAGONIST
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Compound CPG 52364 having formula (I) and pharmaceutically acceptable salts thereof are inhibitors of signaling by Toll-like receptors TLR7, TLR8, and TLR9, and they are useful in treatment of unwanted Immune activity. Pharmaceutical composition including
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Page/Page column 39-40
(2009/01/24)
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- PHARMACOKINETICALLY IMPROVED COMPOUNDS
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The present invention relates to inhibitors of ROCKl and R0CK2 and methods of modulating the pharmacokinetic and/or pharmacodynamic properties of such compounds. Also provided are methods of inhibiting ROCKl and or R0CK2 that are useful for the treatment of disease.
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Page/Page column 138
(2010/11/24)
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- Organic phenyl arsonic acid compounds with potent antileukemic activity
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A series of 12 organic arsonic acid compounds has been synthesized and evaluated against human B-lineage (NALM-6) and T-lineage (MOLT-3) acute lymphoblastic leukemia (ALL) cell lines. The lead compounds 2-trichloromethyl-4-[4′-(4″-phenylazo)phenylarsonic acid]aminoquinazoline (compound 19, PHI-P518; IC50=1.1±0.5 μM against NALM-6 and 2.0±0.8 μM against MOLT-3) and 2-methylthio-4-(2′-phenylarsonic acid)aminopyrimidine (compound 15, PHI-P381; IC50=1.5±0.3 μM against NALM-6 and 2.3±0.5 μM against MOLT-3) exhibited potent antileukemic activity at low micromolar concentrations.
- Liu, Xing-Ping,Narla, Rama Krishna,Uckun, Fatih M.
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p. 581 - 583
(2007/10/03)
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- Phenylarsonic acid compounds with broad-spectrum and potent cytotoxic activity against human cancer cells
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The in vitro cytotoxic activity profile of nine novel phenylarsonic acid (CAS 98-05-5, PAA) compounds against 17 human cancer cell lines including (a) ovarian cancer cell lines ES-2, PA-1, CAOV-3, OVCAR-3, (b) testicular cancer cell lines Ntera-2, Tera-2, N2NICP, 833K, and 64CP, (c) multiple myeloma cell lines ARH77, HS-Sultan, RPMI-8226, and U266, and (d) acute lymphoblastic leukemia (ALL) cell lines NALM-6, MOLT-3, ALL-1, and RS4; 11, was determined by the MTT assay. The lead compounds, 2-methylthio4- [(4′-aminophenylazo)-phenylarsonic acid] pyrimidine (PHI-370) and 2-methylthio-4-(4′-phenylarsonic acid)-aminopyrimidine (PHI-380) caused apoptotic death in all 17 cancer cell lines at low micromolar concentrations, as documented by TUNEL assays and confocal laser scanning microscopy. PHI-380 was also tested and found to be very active against primary tumor cells isolated from surgical biopsy specimens of 14 patients with therapy-refractory non-small cell lung cancer, breast cancer, colon cancer, lymphoma, hepatoblastoma, or Wilm's tumor as well. Because of their broad-spectrum and potent anticancer activity and ability to induce apoptosis in primary tumor cells from therapy-refractory cancer patients, PAA compounds such as PHI-370 and PHI-380 may provide the basis for effective salvage regimens for patients with recurrent cancer.
- Uckun, Fatih M.,D'Cruz, Osmond J.,Liu, Xing-Ping,Narla, Rama Krishna
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p. 428 - 439
(2007/10/03)
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- Therapeutic compounds
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The invention provides novel JAK-3 inhibitors that are useful for treating leukemia and lymphoma. The compounds are also useful to treat or prevent skin cancer, as well as sunburn and UVB-induced skin inflammation. In addition, the compounds of the present invention prevent the immunosuppressive effects of UVB radiation, and are useful to treat or prevent autoimmune diseases, inflammation, and transplant rejection. The invention also provides pharmaceutical compositions comprising compounds of the invention, as well as therapeutic methods for their use.
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- Substituted 2-aryl-4-amino-chinazolines, method for the production and use thereof as medicaments
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Compounds of the formula I in which R1, R2, R3and Ar have the meanings indicated in the claims, are suitable for the production of pharmaceuticals, for example for the prophylaxis and therapy of cardiovascular diseases suc
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- Synthesis and structure-activity relationship of diarylamide urea derivatives as selective inhibitors of the proliferation of human coronary artery smooth muscle cells.
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A series of diarylamide urea derivatives were synthesized and evaluated for their inhibitory activities against human coronary artery smooth muscle cells (SMCs) and human coronary artery endothelial cells (ECs). Compound 2o was superior to the lead compound, Tranilast, in terms of its potency of the inhibitory activity and cell selectivity.
- Ogita, Haruhisa,Isobe, Yoshiaki,Takaku, Haruo,Sekine, Rena,Goto, Yuso,Misawa, Satoru,Hayashi, Hideya
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p. 1865 - 1871
(2007/10/03)
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- 6,7-Dimethoxyquinazolines and therapeutic use thereof
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Quinazoline compounds and methods for the treatment of cancer and for the treatment of allergic reactions.
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- 4-(4′-hydroxyphenyl) amino-6,7-dimethoxyquinazoline to prevent development of colorectal cancer
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The present invention is directed to a method of preventing the development or recurrence of colorectal cancer in a mammal comprising administering to the mammal, an effective cancer preventative amount of 4-(4′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoli
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- Quinazoline formulations and therapeutic use thereof
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Pharmaceutical compositions for parenteral administration of poorly soluble quinazoline compounds in the form of microemulsions or micellar solutions are described. The compositions are useful in treating patients suffering from cancer or having allergic
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- Lipid-lowering quinazoline derivative
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A novel carbonyl-substituted quinazoline, preferably 4-(3′-bromobenzoyl)-6,7-dimethoxyquinazoline (WHI-P164), and methods for lowering blood cholesterol, including reducing total cholesterol and LDL-cholesterol levels by administration of the carbonyl quinazolines and compositions thereof.
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- Synthesis and structure-activity relationship of diarylamide derivatives as selective inhibitors of the proliferation of human coronary artery smooth muscle cells
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A series of diarylamide derivatives were synthesized and evaluated for their inhibitory activities against human coronary artery smooth muscle cells (SMCs) and human coronary artery endothelial cells (ECs). Compound 2w was superior to the lead compound, Tranilast, in terms of the potency of the activity and cell selectivity.
- Gita, Haruhisa,Sobe, Yoshiaki,Akaku, Haruo,Ekine, Rena,Oto, Yuso,Isawa, Satoru,Hayashi, Hideya
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p. 549 - 551
(2007/10/03)
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- Therapeutic compounds
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The invention provides novel JAK-3 inhibitors that are useful for treating leukemia and lymphoma. The compounds are also useful to treat or prevent skin cancer, as well as sunburn and UVB-induced skin inflammation. In addition, the compounds of the present invention prevent the immunosuppressive effects of UVB radiation, and are useful to treat or prevent autoimmune diseases, inflammation, and transplant rejection. The invention also provides pharmaceutical compositions comprising compounds of the invention, as well as therapeutic methods for their use.
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- 6,7-Dimethoxy-4-anilinoquinazolines
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6,7-Dimethoxy-4-anilinoquinaozolines of the formula: or pharmaceutically acceptable acid addition salts thereof are disclosed. These novel compounds are useful for inducing apoptosis and preventing metastases of brain tumor cells.
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- Synthesis and anti-tumor activity of 6,7-dialkoxy-4-phenylamino-quinazolines
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Compounds of the formula: wherein: Rais iodo, (C1-C4)hydroxyalkyl, benzyloxy, OCF3, SCF3, SO3H, SO2F, SO2NR2R3where R2is hydrogen or (
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- 6-alkylamino- and 2,3-dihydro-3′-methoxy-2-phenyl-4-quinazolinones and related compounds: Their synthesis, cytotoxicity, and inhibition of tubulin polymerization
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As part of our continuing search for potential anticancer candidates among 2-phenyl-4-quinolones and 2-phenyl-4-quinazolinones, two series of 6,7,2′,3′,4′,5′-substituted 2-phenyl-4-quinazolinones and 6,2′,3′,4′,5′-substituted 2,3-dihydro-2-phenyl-4-quinazolinones were synthesized and evaluated for cytotoxicity and as inhibitors of tubulin polymerization. In general, a good correlation was found between the two activities. Five of the 6-substituted heterocyclic 2-phenyl-4-quinozolinones (37-51) showed significant cytotoxicity against a panel of human tumor cell lines with EC50 values in the low micromolar to nanomolar concentration ranges. Compound 38 was the most potent of these compounds, as well as the most potent inhibitor of tubulin polymerization in this series. The activity of 38 was in the same range as those of the antimitotic natural products, colchicine, podophyllotoxin, and combretastatin A-4. Substituted 2-phenyl-4-quinazolinones and 2,3-dihydro-2-phenyl-4-quinazolinones also displayed highly selective cytotoxicity against the ovarian cancer 1A9 and P-gp resistant KB-VIN cell lines.
- Hour,Huang,Kuo,Xia,Bastow,Nakanishi,Hamel,Lee
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p. 4479 - 4487
(2007/10/03)
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- Treatment of atherosclerosis in apolipoprotein E-deficient mice with 4- (3'-bromobenzoyl)-6,7-dimethoxyquinazoline (WHI-P164), a potent inhibitor of triglyceride synthesis
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We identified a novel organic compound, 4-(3'-bromobenzoyl)-6,7- dimethoxyquinazoline (compound WHI-P164), as a potent inhibitor of triglyceride (TG) synthesis. In an in vitro model of lipid synthesis, WHI- P164 (but not any one of the three structurally similar control dimethoxyquinazoline compounds) inhibited the accumulation of TG-rich intracellular lipid droplets in Caco-2 human intestinal cells in a concentration-dependent fashion. WHI-P164 caused no acute toxicity associated with morbidity or mortality in mice when administered at dose levels ranging from 0.5 to 80 mg/kg. In pharmacokinetic studies in mice, WHI-P164 was rapidly eliminated from plasma with a terminal elimination half-life of 26.1 ± 1.3 min after intraperitoneal administration and 33.3 ± 11.3 min after intravenous administration. Treatment with 40 mg/kg WHI-P164 (but not one of three structurally similar control dimethoxyquinazoline compounds) administered intraperitoneally once daily for 7 consecutive treatment days blocked the in vivo hepatic TG synthesis in both apoE-deficient and wild-type C57B1/6 mice. In apoE-deficient mice maintained on a high-fat/high- cholesterol Western diet, WHI-P164 substantially reduced the lipid accumulation in the liver after 7 days of treatment and the lipid accumulation in the aorta after 1 month of treatment. Our results in apoE- deficient mice show that lipid accumulation in hepatocytes and foam cells are related events, and inhibiting TG synthesis with WHI-P164 offers an effective means to treat atherosclerosis.
- Trieu, Vuong N.,Liu, Xing-Ping,Chen, Chun-Lin,Uckun, Fatih M.
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p. 179 - 188
(2007/10/03)
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- JAK-3 inhibitors for treating allergic disorders
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Inhibitors of JAK3 kinase for the treatment of allergy inhibit mast cell degranulation an dmediator release.
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- 2-oxo-1-(((substituted sulfonyl)amino)-carbonyl)azetidines
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Antibacterial activity is exhibited by β-lactams having a 3-acylamino substituent and having in the 1-position an activating group of the formula STR1 wherein R is
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