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Shilin Yang - One of the best experts on this subject based on the ideXlab platform.
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cytotoxicity hemolytic toxicity and mechanism of action of pulsatilla saponin d and its synthetic derivatives
Journal of Natural Products, 2017Co-Authors: Zhong Chen, Huaqing Duan, Xiaohang Tong, Susan L Morrisnatschke, Shilin YangAbstract:The strong hemolytic toxicity of pulsatilla saponin D (1, HD50 6.3 μM) has hampered its clinical development as an injectable anticancer agent. To combat this challenge, 17 new derivatives of 1 with ring C, C-28, or C-3 modifications were synthesized and evaluated for cytotoxicity against several selected human tumor lines, as well as for hemolytic toxicity against rabbit erythrocytes. Structure–activity relationship (SAR) and structure–toxicity relationship (STR) correlations were also elucidated. Compared to the lead compound 1, the hemolytic activity of all 17 derivatives dropped dramatically. Notably, compound 14 exhibited significant cytotoxicity toward A549 human lung cancer cells (IC50 2.8 μM) in a dose-dependent manner without hemolytic toxicity (HD50 > 500 μM). Molecular studies indicated that 14 induced typical G1 cell cycle arrest and apoptosis in A549 cells, and Western blot assays suggested that both intrinsic and extrinsic apoptosis pathways were activated by 14. Collectively, compound 14 ma...
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the derivatives of pulsatilla saponin a a bioactive compound from pulsatilla chinensis their synthesis cytotoxicity haemolytic toxicity and mechanism of action
European Journal of Medicinal Chemistry, 2017Co-Authors: Zhong Chen, Huaqing Duan, Xiaohang Tong, Shilin Yang, Yulin FengAbstract:Abstract The strong haemolytic toxicity of Pulsatilla saponin A (PSA) has hampered its clinical development as an injectable anticancer agent. To circumvent this challenge, twenty PSA derivatives with C ring or C-28 or C-3 modifications were synthesized and evaluated for cytotoxicity against seven selected human tumor lines, as well as for haemolytic toxicity. Structure-activity relationship (SAR) and structure-toxicity relationship (STR) correlations were also elucidated. Compared with PSA, compound 22 showed a better balance between haemolytic toxicity (HD50 > 500 μM) and cytotoxicity toward lung cancer cells A549 (IC50 = 4.68 μM). Molecular studies indicated that 22 was liked to lead to G1 cell cycle arrest and therefore, 22 may be a potent antitumor drug candidate.
Yasuo Isomura - One of the best experts on this subject based on the ideXlab platform.
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spiro substituted piperidines as neurokinin receptor antagonists ii syntheses and nk2 receptor antagonistic activities of n 2 aryl 4 spiro substituted piperidin 1 yl butyl carboxamides
Chemical & Pharmaceutical Bulletin, 1998Co-Authors: Hirokazu Kubota, Akio Kakefuda, Hitoshi Nagaoka, Osamu Yamamoto, Ken Ikeda, Makoto Takeuchi, Tadao Shibanuma, Yasuo IsomuraAbstract:In the course of our research on spiro-compounds as neurokinin receptor antagonists, N-[2-aryl-4-(spiro-substituted piperidin-1'-yl)butyl]carboxamides were designed, based on YM-35375 (3) as a lead compound, and evaluated for NK2 receptor-antagonistic activities. Some derivatives inhibited the binding of radio-labeled neurokinin A to the NK2 receptor with IC50 values at the level of 10-9M. Among these compounds, (±)-1'-[4-(N-benzoyl-N-methylamino)-3-(3, 4-dichlorophenyl)butyl]spiro[benzo[c]thiophene-1(3H), 4'-piperidine] 2-oxide (58, YM-38336) showed 10 times more potent NK2 receptor binding affinity than compound 3 (IC50 values of 8.9 and 84nM, respectively). It showed more potent inhibitory activity (ID50 20μg/kg (i.v.)) against [β-Ala8]-NKA(4-10)-induced bronchoconstriction in guinea pigs than compound 3 (ID50 41μg/kg (i.v.)). This compound was also effective intraduodenally in the same model, exhibiting an ID50 value of 0.41μg/kg.
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spiro substituted piperidines as neurokinin receptor antagonists i design and synthesis of n 2 3 4 dichlorophenyl 4 spiro isobenzofuran 1 3h 4 piperidin 1 yl butyl n methylbenzamide ym 35375 as a new lead compound for novel neurokinin receptor antago
Chemical & Pharmaceutical Bulletin, 1998Co-Authors: Hirokazu Kubota, Ken Ikeda, Makoto Takeuchi, Tadao Shibanuma, Masahiro Fujii, Yasuo IsomuraAbstract:Analysis of the structural requirements of compound 1 (SR48968), a potent NK2 receptor antagonist, revealed that the 4-phenyl group of the piperidine is essential for binding with the NK2 receptor and occupies an equatorial position. Energy calculation of a variety of substituted 4-phenyl piperidines revealed that spiro[isobenzofuran-1(3H), 4'-piperidine] possesses a conformationally restricted equatorial phenyl group. Our compound 12 (YM-35375) possessing this spiro-substituted piperidine bound to the NK2 receptor with an IC50 value of 84nM and to NK1 receptor with an IC50 value of 710nM. It showed more potent inhibitory activity (ID50 41μg/kg (i.v.)) against [β-Ala8]-NKA(4-10)-induced bronchoconstriction in guinea pigs than (±)-SR48968 (ID50 68μg/kg (i.v.)). YM-35375 may be a new lead compound for novel NK2 receptor antagonists or NK1-NK2 dual antagonists.
Joao B Calixto - One of the best experts on this subject based on the ideXlab platform.
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bulgarian propolis induces analgesic and anti inflammatory effects in mice and inhibits in vitro contraction of airway smooth muscle
Journal of Pharmacological Sciences, 2003Co-Authors: Niraldo Paulino, Andreia P Dantas, Vassya Bankova, Daniela Taggliari Longhi, Amarilis Scremin, Solange L De Castro, Joao B CalixtoAbstract:ABSTRACT Propolis is a bee product, which has long been used in folk medicine for the management of different diseases. In this study we evaluated the analgesic and anti-inflammatory effects of a standard ethanolic extract of Bulgarian propolis (Et-Blg) in mice and its in vitro effect on airway smooth muscle. Et-Blg inhibited acetic acid-induced abdominal contortions with an ID50 = 7.4 ± 0.7 mg · kg-1. In the formalin test, the extract caused a significant reduction in pain in mice treated with 100 mg · kg-1 Et-Blg during the neurogenic phase and for the inflammatory phase with all doses of the extract, with an ID50 = 2.5 ± 0.4 mg · kg-1. Et-Blg inhibited also the capsaicin-induced ear edema in mice; however, this extract was ineffective when assessed in the tail-flick and hot-plate thermal assays. The analgesic effect of Et-Blg was associated with the inhibition of inflammatory responses and not to a simple irritation of nervous terminals. In vitro, this extract inhibited the contraction of trachea smooth muscle induced by histamine (IC50 = 50 ± 5 μg · mL-1), capsaicin (IC50 = 26.8 ± 3 μg · mL-1), 80 mM KCl (IC50 = 27.8 ± 3 μg · mL-1), and carbachol (IC50 = 54 ± 2 μg · mL-1).
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antinociceptive properties of the hydroalcoholic extract and preliminary study of a xanthone isolated from polygala cyparissias polygalaceae
Life Sciences, 1997Co-Authors: Rafael Campos, Adair R S Santos, Tânia R Pinheiro, Moacir Geraldo Pizzolatti, Valdir Cechinel Filho, Franco Delle Monache, Rosendo A Yunes, Joao B CalixtoAbstract:Abstract Polygala cyparissias (Polygalaceae) grows abundantly on Brazil's Atlantic coast, belonging to the typical underbrush vegetation of dunes and have been used in folk medicine for treatment of several diseases, such as disturbances of bowel and kidney. The hydroalcoholic extract of P. cyparissias (HE, 3 to 60 mg kg−1, i.p. or 25 to 200 mg kg−1, p.o.) produced significant and graded inhibition of acetic acid-induced abdominal constrictions, with mean ID50 values of 6 and 72 mg kg−1, respectively. The HE (at this same range of doses) also produced dose-related inhibition of both the early and the late phase of formalin-induced licking. The calculated mean ID50 values for the early phase were: > 60 and > 200 mg kg−1, while for the late phase they were 11 and 101 mg kg−1, respectively, by i.p. and p.o. routes. The HE also caused dose-related inhibition of formalin-induced edema formation (P nmol paw ) and substance P (10 nmol paw )-induced hyperalgesia in the rat paw, with mean ED50 values of 122 and 121 mg kg−1, respectively, but was ineffective in the hot-plate model of nociception. The antinociception caused by the HE, in contrast to that of morphine (5 mg kg−1, s.c.), was not reversed by naloxone (5 mg kg−1, i.p.) when assessed in the acetic acid writhing test. The HE, at antinociceptive doses, did not affect motor coordination of animals when assessed in the rota-rod model. The xanthone isolated from P. cyparissias, identified as 1,7-dihydroxy-2,3-dimethoxy xanthone (0.3 to 30 mg kg−1, i.p.), produced dose-related inhibition of acetic acid-induced abdominal constriction, with mean ID50 value of 1.5 mg kg−1. These data show that the active principle(s) present in the HE of P. cyparissias, elicited pronounced antinociception when assessed by i.p or p.o. routes, against both inflammatory and neurogenic nociception, and was able to prevent bradykinin and substance P-induced hyperalgesia. Its precise mechanism of action still remains unclear.
Neil Richard Ackerman - One of the best experts on this subject based on the ideXlab platform.
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anti inflammatory and safety profile of dup 697 a novel orally effective prostaglandin synthesis inhibitor
Journal of Pharmacology and Experimental Therapeutics, 1990Co-Authors: K R Gans, W Galbraith, Richard J Roman, S B Haber, J S Kerr, W K Schmidt, W E Hewes, C. Smith, Neil Richard AckermanAbstract:DuP 697 (5-bromo-2[4-fluorophenyl]-3-[4-methylsulfonylphenyl]-thiophene) is a potent inhibitor of paw swelling in nonestablished and established adjuvant arthritis in rats (ED50 = 0.03 and 0.18 mg/kg/day, respectively). DuP 697 had no effect on phenylquinone writhing in rats (ED50 greater than 100 mg/kg), but was analgetic against inflammation-related pain in the Randall-Selitto assay (ED30 = 3.5 mg/kg) and was a very potent antipyretic agent (ED50 = 0.05 mg/kg). The drug was not ulcerogenic in rats at single doses up to 400 mg/kg. DuP 697 (5 mg/kg i.v.) did not alter renal blood flow or the renal vascular response to angiotensin II in furosemide-pretreated, volume-depleted rats. In contrast, indomethacin (5 mg/kg i.v.) decreased renal blood flow and potentiated the renal vascular response to angiotensin II in these animals. DuP 697 was a moderate inhibitor of bull seminal vesicle prostaglandin (PG) synthesis (IC50 = 2.4 X 10(-5) M) and a potent inhibitor of rat brain PG synthesis (IC50 = 4.5 X 10(-6) M) but was ineffective against rat kidney PG synthesis (IC50 7.5 X 10(-5) M). These differential effects of DuP 697 on PG synthesis by various tissues may account for its high potency as an anti-inflammatory and antipyretic agent and its minimal toxicity profile.
Paolo Manitto - One of the best experts on this subject based on the ideXlab platform.
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anti inflammatory activity of maytenus senegalensis root extracts and of maytenoic acid
Phytomedicine, 2007Co-Authors: S Sosa, Carlo F Morelli, A Tubaro, Paola Cairoli, Giovanna Speranza, Paolo ManittoAbstract:Abstract Maytenus senegalensis (Lam.) Excell (Celastraceae) root extracts were investigated for their topical anti-inflammatory properties by measuring the inhibition of the Croton oil-induced ear oedema in mice. The highest anti-inflammatory activity was detected in the chloroform extract, which reduced the oedematous response with a potency similar to that of the NSAID reference drug indomethacin (ID50=84 and 93 μg/cm2, respectively). Fractionation of the chloroform and of the hexane extracts led to the isolation of maytenoic acid (1), which exhibited a dose-dependent antiphlogistic effect (ID50=0.11 μmol/cm2) twice that of indomethacin (ID50=0.26 μmol/cm2) and only three times lower than that of hydrocortisone (ID50=0.04 μmol/cm2).
