Ac-Hyp-Ser-Ser-Chg-Gln-Ser-OH | 474116-74-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: Ac-Hyp-Ser-Ser-Chg-Gln-Ser-OH
• 英文别名: (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,4R)-1-acetyl-4-hydroxypyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-2-cyclohexylacetyl]amino]-5-amino-5-oxopentanoyl]amino]-3-hydroxypropanoic acid
• CAS: 474116-74-0
• 化学式: C₂₉H₄₇N₇O₁₃
• 分子量: 701.731
• InChiKey: DMWYHYSPPYYUCH-UEHQSFIUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.7
• 重原子数：
  49
• 可旋转键数：
  18
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  327
• 氢给体数：
  11
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  Ac-Hyp-Ser-Ser-Chg-Gln-Ser-OH 、 4-O-(glycyl)-des-acetyl vinblastine TFA salt 在 N-甲基吗啉 、 AtH₂⁽¹⁺⁾*HO^(1-) 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 N-甲基吡咯烷酮 为溶剂， 反应 20.0h， 以41 mg的产率得到4-O-(Ac-Hyp-Ser-Ser-Chg-Gln-Ser-Gly)-des-acetyl vinblastine
  参考文献：
  名称：

  Design and Synthesis of a Pro-Drug of Vinblastine Targeted at Treatment of Prostate Cancer with Enhanced Efficacy and Reduced Systemic Toxicity

  摘要：

  Chemotherapy of prostate cancer with antimitotic agents such as vinblastine and doxorubicin is only marginally effective, due to dose-limiting systemic toxicity. Herein we report the development of peptidyl conjugate 5 of the cytotoxic agent vinblastine (1), along with the results of its in vitro and in vivo evaluation as a pro-drug targeted at prostate cancer cells. Prostate-derived tumors are known to produce significant amounts of prostate specific antigen (PSA), a serine protease with chymotrypsin-like properties. Earlier work in these laboratories established that an appropriately engineered peptidyl pro-drug will release active cytotoxic agent strictly within the microenvironment of the tumor tissue (Garsky, V. M., et al. J. Med. Chem. 2001, 44, 4216-4224). Conjugate 5, which features an octapeptide segment attached by an ester linkage at the 4-position of vinblastine (1), undergoes rapid cleavage by PSA (T-1/2 = 12 min) between the Gln and Ser residues. In nude mouse xenograft studies, 5 reduced circulating PSA levels by 99% and tumor weight by 85% at a dose just below its MTD. By contrast, the putative end-point metabolite, the cytotoxic agent des-acetyl vinblastine (1b), was ineffective in reducing PSA levels and tumor burden at its maximum tolerated doses. Additional data from metabolism studies on 5 support the supervention of a novel in vivo processing mechanism, the spontaneous release of 1b from a dipeptidyl intermediate driven by favorable diketopiperazine formation.

  DOI：

  10.1021/jm020139f
• 作为产物：
  描述：

  FMOC-O-叔丁基-L-丝氨酸 、 Fmoc-N-三苯甲基-L-谷氨酰胺 、 溶剂黄146 、 Fmoc-L-4-羟基脯氨酸 、 芴甲氧羰酰基环己基甘氨酸 以80%的产率得到Ac-Hyp-Ser-Ser-Chg-Gln-Ser-OH
  参考文献：
  名称：

  Design and Synthesis of a Pro-Drug of Vinblastine Targeted at Treatment of Prostate Cancer with Enhanced Efficacy and Reduced Systemic Toxicity

  摘要：

  Chemotherapy of prostate cancer with antimitotic agents such as vinblastine and doxorubicin is only marginally effective, due to dose-limiting systemic toxicity. Herein we report the development of peptidyl conjugate 5 of the cytotoxic agent vinblastine (1), along with the results of its in vitro and in vivo evaluation as a pro-drug targeted at prostate cancer cells. Prostate-derived tumors are known to produce significant amounts of prostate specific antigen (PSA), a serine protease with chymotrypsin-like properties. Earlier work in these laboratories established that an appropriately engineered peptidyl pro-drug will release active cytotoxic agent strictly within the microenvironment of the tumor tissue (Garsky, V. M., et al. J. Med. Chem. 2001, 44, 4216-4224). Conjugate 5, which features an octapeptide segment attached by an ester linkage at the 4-position of vinblastine (1), undergoes rapid cleavage by PSA (T-1/2 = 12 min) between the Gln and Ser residues. In nude mouse xenograft studies, 5 reduced circulating PSA levels by 99% and tumor weight by 85% at a dose just below its MTD. By contrast, the putative end-point metabolite, the cytotoxic agent des-acetyl vinblastine (1b), was ineffective in reducing PSA levels and tumor burden at its maximum tolerated doses. Additional data from metabolism studies on 5 support the supervention of a novel in vivo processing mechanism, the spontaneous release of 1b from a dipeptidyl intermediate driven by favorable diketopiperazine formation.

  DOI：

  10.1021/jm020139f

文献信息

• Design and Synthesis of a Pro-Drug of Vinblastine Targeted at Treatment of Prostate Cancer with Enhanced Efficacy and Reduced Systemic Toxicity
  作者：Stephen F. Brady、Joseph M. Pawluczyk、Patricia K. Lumma、Dong-Mei Feng、Jenny M. Wai、Raymond Jones、Deborah DeFeo-Jones、Bradley K. Wong、Cynthia Miller-Stein、Jiunn H. Lin、Allen Oliff、Roger M. Freidinger、Victor M. Garsky

  DOI：10.1021/jm020139f

  日期：2002.10.1

  Chemotherapy of prostate cancer with antimitotic agents such as vinblastine and doxorubicin is only marginally effective, due to dose-limiting systemic toxicity. Herein we report the development of peptidyl conjugate 5 of the cytotoxic agent vinblastine (1), along with the results of its in vitro and in vivo evaluation as a pro-drug targeted at prostate cancer cells. Prostate-derived tumors are known to produce significant amounts of prostate specific antigen (PSA), a serine protease with chymotrypsin-like properties. Earlier work in these laboratories established that an appropriately engineered peptidyl pro-drug will release active cytotoxic agent strictly within the microenvironment of the tumor tissue (Garsky, V. M., et al. J. Med. Chem. 2001, 44, 4216-4224). Conjugate 5, which features an octapeptide segment attached by an ester linkage at the 4-position of vinblastine (1), undergoes rapid cleavage by PSA (T-1/2 = 12 min) between the Gln and Ser residues. In nude mouse xenograft studies, 5 reduced circulating PSA levels by 99% and tumor weight by 85% at a dose just below its MTD. By contrast, the putative end-point metabolite, the cytotoxic agent des-acetyl vinblastine (1b), was ineffective in reducing PSA levels and tumor burden at its maximum tolerated doses. Additional data from metabolism studies on 5 support the supervention of a novel in vivo processing mechanism, the spontaneous release of 1b from a dipeptidyl intermediate driven by favorable diketopiperazine formation.