- Discovery of potent 2,4-difluoro-linker poly(ADPribose) polymerase 1 inhibitors with enhanced water solubility and in vivo anticancer efficacy
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Poly (ADP-ribose) polymerase 1 (PARP1) is overexpressed in a variety of cancers, especially in breast and ovarian cancers; tumor cells that are deficient in breast cancer gene 1/2 (BRCA1/2) are highly sensitive to PARP1 inhibition. In this study, we identified a series of 2,4-difluorophenyl-linker analogs (15-55) derived from olaparib as novel PARP1 inhibitors. Four potent analogs 17, 43, 47, and 50 (IC50=2.2-4.4 nmol/L) effectively inhibited the proliferation of Chinese hamster lung fibroblast V-C8 cells (IC50=3.2-37.6 nmol/L) in vitro, and showed specificity toward BRCA-deficient cells (SI=40-510). The corresponding hydrochloride salts 56 and 57 (based on 43 and 47) were highly water soluble in pH=1.0 buffered salt solutions (1628.2 μg/mL, 2652.5 μg/mL). In a BRCA1-mutated xenograft model, oral administration of compound 56 (30 m?kg-1d-1, for 21 d) exhibited more prominent tumor growth inhibition (96.6%) compared with the same dose of olaparib (56.3%); in a BRCA2-mutated xenograft model, oral administration of analog 43 (10 m?kg-1d-1, for 28 d) significantly inhibited tumor growth (69.0%) and had no negative effects on the body weights. Additionally, compound 56 exhibited good oral bioavailability (F=32.2%), similar to that of olaparib (F=45.4%). Furthermore, the free base 43 of the hydrochloride salt 56 exhibited minimal hERG inhibition activity (IC50=6.64 μmol/L). Collectively, these data demonstrate that compound 56 may be an excellent drug candidate for the treatment of cancer, particularly BRCA-deficient tumors.
- Chen, Wen-Hua,Song, Shan-Shan,Qi, Ming-Hui,Huan, Xia-Juan,Wang, Ying-Qing,Jiang, Hualiang,Ding, Jian,Ren, Guo-Bin,Miao, Ze-Hong,Li, Jian
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- 2. 4 - difluoro - 5 - (phthalazinone - 1 - methyl) - benzoyl piperazine compound and use thereof
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The invention relates to a 2,4-difluoro-5-(phthalazone-1-methyl)-benzoyl piperazine compound and application of the 2,4-difluoro-5-(phthalazone-1-methyl)-benzoyl piperazine compound. Specifically, the invention discloses a compound of the structure shown in the formula I, wherein the definition of the compound of the structure shown in the formula I can be seen in the specification. The compound has the excellent PARP activity inhibitory effect and the excellent antitumor effect.
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- Optimization of potency and pharmacokinetics of tricyclic indole derived inhibitors of HCV NS5B polymerase. Identification of ester prodrugs with improved oral pharmacokinetics
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HCV infections are the leading causes for hepatocellular carcinoma and liver transplantation in the United States. Recent advances in drug discovery have identified direct acting antivirals which have significantly improved cure rates in patients. Current
- Venkatraman, Srikanth,Velazquez, Francisco,Gavalas, Stephen,Wu, Wanli,Chen, Kevin X.,Nair, Anilkumar G.,Bennett, Frank,Huang, Yuhua,Pinto, Patrick,Jiang, Yueheng,Selyutin, Oleg,Vibulbhan, Bancha,Zeng, Qingbei,Lesburg, Charles,Duca, Jose,Heimark, Larry,Huang, Hsueh-Cheng,Agrawal, Sony,Jiang, Chuan-Kui,Ferrari, Eric,Li, Cheng,Kozlowski, Joseph,Rosenblum, Stuart,Shih, Neng-Yang,George Njoroge
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p. 447 - 458
(2014/01/17)
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- 5, 6-RING ANNULATED INDOLE DERIVATIVES AND USE THEREOF
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The present invention relates to 5,6-ring annulated indole derivatives of the formula (I), compositions comprising at least one 5,6-ring annulated indole derivatives, and methods of using the 5,6-ring annulated indole derivatives for treating or preventing a viral infection or a virus-related disorder in a patient.
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- TRICYCLIC INDOLE DERIVATIVES AND METHODS OF USE THEREOF
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The present invention relates to Tricyclic Indole Derivatives, compositions comprising at least one Tricyclic Indole Derivatives, and methods of using the Tricyclic Indole Derivatives for treating or preventing a viral infection or a virus-related disorder in a patient
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Page/Page column 69; 70
(2010/01/07)
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- TETRACYCLIC INDOLE DERIVATIVES AND METHODS OF USE THEREOF
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The present invention relates to Tetracyclic Indole Derivatives, compositions comprising at least one Tetracyclic Indole Derivative, and methods of using the Tetracyclic Indole Derivatives for treating or preventing a viral infection or a virus-related disorder in a patient.
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Page/Page column 161-162
(2009/04/25)
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- 2,3-SUBSTITUTED AZAINDOLE DERIVATIVES FOR TREATING VIRAL INFECTIONS
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The present invention relates to 2,3-Substituted Azaindole Derivatives, compositions comprising at least one 2,3-Substituted Azaindole Derivatives, and methods of using the 2,3-Substituted Azaindole Derivatives for treating or preventing a viral infection or a virus-related disorder in a patient.
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Page/Page column 101
(2009/04/25)
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- SUBSTITUTED INDOLE DERIVATIVES AND METHODS OF USE THEREOF
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The present invention relates to Substituted Indole Derivatives, compositions comprising at least one Substituted Indole Derivative, and methods of using these Substituted Indole Derivatives for treating or preventing a viral infection or a virus-related disorder in a patient.
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Page/Page column 203
(2009/04/25)
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- 4, 5-RING ANNULATED INDOLE DERIVATIVES FOR TREATING OR PREVENTING OF HCV AND RELATED VIRAL INFECTIONS
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The present invention relates to 4, 5 - ring annulated indole derivatives of formula ( I ), compositions comprising at leas t one 4, 5 - ring annulated indole derivatives, and methods of using the 4, 5 - ring annulated ^ndole derivatives for treating or preventing a viral inf ection or a virus - related disorder in a patient, (I) wherein ring Z of formula (I), is cyclohexyl, cyclohexenyl, 6-membered heterocycloalkyl, 6- membered heterocycloalkenyl, 6-membered aryl or 6-membered heteroaryl, wherein R1, R2, R3, R6. R7 and R10 are as described herein.
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- 4,5-RING ANNULATED INDOLE DERIVATIVES FOR TREATING OR PREVENTING OF HCV AND RELATED VIRAL INFECTIONS
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The present invention relates to 4,5-ring annulated indole derivatives, compositions comprising at least one 4,5-ring annulated indole derivatives, and methods of using the 4,5-ring annulated indole derivatives for treating or preventing a viral infection or a virus-related disorder in a patient. Wherein ring Z, of formula (I), is a cyclopentyl, cyclopentenyl, 5-membered heterocycloalkyl, 5-membered heterocycloalkenyl or 5-membered heteroaryl ring.
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- Design and synthesis of N-nonpolar nucleobase dipeptides: Application of the Ugi reaction for the preparation of dipeptides havingfluoroarylalkyl groups appended to the nitrogen atom
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A single-step one-pot synthesis based on the Ugi four-component condensation of previously unknown dipeptides, 2,3,4 and 5, having afluoroaromatic group appended to the nitrogen atom, is described. The series of dipeptides produced here can be viewed as nonpolar nucleobase dipeptides since the difluorotoluene nucleoside 1 is a well known nonpolar analogue of natural thymidine. A mixture of N-protected amino acids 7, fluorophenethylamines 6, isocyanides 8, and acetone or paraformaldehyde are stirred in methanol in the presence of 3 A molecular sieves to furnish the N-fluoroarylethyl-Aib- or -Gly-containing dipeptides 2 or 3, in moderate yields. The dipeptides 2d and 3b, having a cyclohex-1-enamide moiety, are deprotected readily with 3 M HCl in THF to a3ord the free dipeptides in high yields. The N-fluoroarylmethyl-Aib- or -Gly-containingβ-alanyl dipeptides 4 or 5, designed based on the structure of 2′,5′-linked isoDNA, are also synthesized in a similar fashion to the preparation of 2, in moderate to good yields as both protected and free dipeptides.
- Das, Biplab Kumar,Shibata, Norio,Takeuchi, Yoshio
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p. 197 - 206
(2007/10/03)
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- Synthesis of nonpolar peptide nucleic acid monomers containing fluoroaromatics
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A general strategy for the synthesis of nonpolar peptide nucleic acid monomers containing fluoroaromatics (F-PNA) is described. These compounds have been designed as hybrid analogues of the difluorotoluene nucleoside, F (1) with PNA. Fluorophenylacetic ac
- Shibata,Biplab Kumar Das,Honjo,Takeuchi
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p. 1605 - 1611
(2007/10/03)
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- Application of the Ugi four-component condensation reaction for the synthesis of α,α- and α,β-dipeptides substituted with fluoroarylalkyl pendent groups
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The application of the Ugi four-component condensation reaction for the synthesis of α,α- and α,β-dipeptides substituted with fluoroarylalkyl pendent groups was reported. The Ugi reaction using readily available fluorophenethyl amines was examined in the analysis. The method was applicable to the peptides containing a variety of amino acids attached to a diverse series of fluoroarylalkyl groups.
- Shibata, Norio,Das, Biplab Kumar,Takeuchi, Yoshio
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p. 4234 - 4236
(2007/10/03)
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