- Development of novel phenoxy-diketopiperazine-type plinabulin derivatives as potent antimicrotubule agents based on the co-crystal structure
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The co-crystal structure of Compound 6b with tubulin was prepared and solved for indicating the binding mode and for further optimization. Based on the co-crystal structures of tubulin with plinabulin and Compound 6b, a total of 27 novel A/B/C-rings plinabulin derivatives were designed and synthesized. Their biological activities were evaluated against human lung cancer NCI-H460 cell line. The optimum phenoxy-diketopiperazine-type Compound 6o exhibited high potent cytotoxicity (IC50 = 4.0 nM) through SAR study of three series of derivatives, which was more potent than plinabulin (IC50 = 26.2 nM) and similar to Compound 6b (IC50 = 3.8 nM) against human lung cancer NCI-H460 cell line. Subsequently, the Compound 6o was evaluated against other four human cancer cell lines. Both tubulin polymerization assay and immunofluorescence assay showed that Compound 6o could inhibit microtubule polymerization efficiently. Furthermore, theoretical calculation of the physical properties and molecular docking were elucidated for these plinabulin derivatives. The binding mode of Compound 6o was similar to Compound 6b based on the result of molecular docking. The theoretical calculated LogPo/w and PCaco of Compound 6o were better than Compound 6b, which could enhance its cytostatic activity. Therefore, Compound 6o might be developed as a novel potent anti-microtubule agent.
- Ding, Zhongpeng,Ma, Mingxu,Zhong, Changjiang,Wang, Shixiao,Fu, Zhangyu,Hou, Yingwei,Liu, Yuqian,Zhong, Lili,Chu, Yanyan,Li, Feng,Song, Cai,Wang, Yuxi,Yang, Jinliang,Li, Wenbao
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- TDO2 INHIBITORS
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Presently provided are inhibitors of cellularly expressed TDO2 and pharmaceutical compositions thereof, useful for modulating an activity of tryptophan 2, 3 dioxygenase; treating immunosuppression; treating a medical conditions that benefit from the inhibition of tryptophan degradation; enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent; and treating tumor-specific immunosuppression associated with cancer.
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Paragraph 2120
(2017/07/14)
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- AMINOQUINAZOLINE DERIVATIVES AND THEIR SALTS AND METHODS OF USE
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The present invention relates to the field of medicine. Provided herein are aminoquinazoline derivatives, their salts and pharmaceutical formulations useful in modulating the protein tyrosine kinase activity, and in modulating inter- and/or intra-cellular signaling. Also provided herein are pharmaceutically acceptable compositions comprising the aminoquinazoline compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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- AMINOQUINAZOLINE DERIVATIVES AND THEIR SALTS AND METHODS OF USE
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The present invention relates to the field of medicine. Provided herein are aminoquinazoline derivatives, their salts and pharmaceutical formulations useful in modulating the protein tyrosine kinase activity, and in modulating inter-and/or intra-cellular signaling. Also provided herein are pharmaceutically acceptable compositions comprising the aminoquinazoline compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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Paragraph 00342
(2013/06/05)
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- PYRIDO [4,3-d] PYRIMIDIN-4 (3H) -ONE DERIVATIVES AS CALCIUM RECEPTOR ANTAGONISTS
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The present invention is directed to novel pyrido[4,3-d]pyrimidin-4(3H)-one derivatives and pharmaceutically acceptable salts thereof of structural formula I wherein the variables R1, R2, R3, R4 and R5 are as described herein. Also provided are pharmaceutical compositions comprising the compounds of formula I as well as methods of treatment employing compounds of formula I to treat a disease or disorder characterized by abnormal bone or mineral homeostasis such as hypoparathyroidism, osteoporosis, osteopenia, periodontal disease, Paget's disease, bone fracture, osteoarthritis, rheumatoid arthritis, and humoral hypercalcemia of malignancy.
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Page/Page column 23
(2008/06/13)
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- Stereoselective synthesis of swainsonines from pyridines
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An efficient synthesis of (-)-swainsonine and (-)-2,8a-di-epi-swainsonine was developed starting from readily available 2-pyridinecarbaldehyde and 3-hydroxypyridine. In particular, it was demonstrated that the mixture of simple indolizidines, i.e. lentigi
- Heimg?rtner, Gerres,Raatz, Dirk,Reiser, Oliver
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p. 643 - 655
(2007/10/03)
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- New highly active taxoids from 9β-dihydrobaccatin-9,10-acetals. Part 4
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It was shown that a new taxane analogue 3, which exhibited both in vitro antitumor activity and in vivo efficacy by both iv and po administration, was prone to be metabolized by human liver microsomes. We identified a major metabolite, M-1, generated by h
- Takeda, Yasuyuki,Uoto, Kouichi,Chiba, Jun,Horiuchi, Takao,Iwahana, Michio,Atsumi, Ryo,Ono, Chiho,Terasawa, Hirofumi,Soga, Tsunehiko
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p. 4431 - 4447
(2007/10/03)
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- ORTHO SUBSTITUTED AROMATIC COMPOUNDS USEFUL AS ANTAGONISTS OF THE PAIN ENHANCING EFFECTS OF E-TYPE PROSTAGLANDINS
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The invention relates to compounds of the formula (I): STR1 wherein A, B and D are various ring systems such as phenyl, R. sup.1 includes carboxy, R 3 is hydrogen or C 1-4 alkyl and Z is a linking group such as--(CH(R 5)) m--wherein m is 2, 3 or 4, and R 5 includes hydrogen and methyl; and pharmaceutically acceptable salts and in vivo hydrolysable esters or amides thereof, processes for preparing these compounds, pharmaceutical compositions comprising them, and their use in the treatment of pain.
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- Synthesis and β-adrenoreceptor blocking activity of [[3-(alkylamine)-2-hydroxypropyl]oximino]pyridines and O[3-(alkylamine)-2-hydroxypropyl]methylpyridine ketone oximes derivatives
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[[3-(alkylamine)-2-hydroxypropyl]-2-oximino]pyridines and O-[3-(alkylamine)-2-hydroxypropyl]methylpyridine ketone oximes 5a-o were synthesized by a solid-liquid phase-transfer reaction, and their β-adrenoreceptor blocking activity was evaluated in vitro a
- Manna,Bolasco,Bizzarri,Lena,Chimenti,Filippelli,Palla,Fontana
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p. 579 - 587
(2007/10/03)
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- Guanylhydrazones of 3-substituted 2-pyridinecarboxaldehyde and of (2-substituted 3-pyridinyloxy) acetaldehyde as prostanoid biosynthesis and platelet aggregation inhibitors
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Some guanylhydrazones of (3-benzyloxy)-2-pyridinecarboxaldehyde and of (2-substituted 3-pyridinyloxy)acetaldehyde were prepared in order to evaluate their possible activity as inhibitors of prostanoid biosynthesis in human serum.Only those products of the second group without the carboxylic function reduced prostanoid generation in vitro at the highest concentration; they also inhibited platelet aggregation induced by arachidonic acid and U-46619.The results suggest that these compounds are both inhibitors of cyclooxygenase and cyclic endoperoxides/TxA2 platelet receptor antagonists.
- Desideri, N,Sestili, I,Manarini, S,Cerletti, C,Stein, ML
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p. 455 - 460
(2007/10/02)
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- Dihydropyridines and their use in the treatment of asthma
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New dihydropyridines are described. These compounds are useful in the treatment of asthma.
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