Designing Synthetic, Sulfated Glycosaminoglycan Mimetics That Are Orally Bioavailable and Exhibiting In Vivo Anticancer Activity.
Designing Synthetic, Sulfated Glycosaminoglycan Mimetics That Are Orally Bioavailable and Exhibiting In Vivo Anticancer Activity.
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DOI：
10.1021/acs.jmedchem.2c01511
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发表时间：
2023-01-26
影响因子：
7.3
通讯作者：
Desai, Umesh R.
中科院分区：
文献类型：
--
作者：
Morla, Shravan;Ravikumar, Ongolu;O'Hara, Connor;Boothello, Rio;Vera, Alberto;Abdelfadiel, Elsamani I.;Fayyad, Rawan;Afosah, Daniel K.;Sharon, Chetna;Fernandez, Leopoldo;Shah, Syed Ammer;Patel, Bhaumik B.;Desai, Umesh R.
硫酸化糖胺聚糖（GAG）或其合成模拟物由于其大量的阴离子硫酸根基团而不被有利地视为口服生物可利用的药物。设计一种口服递送这种高度硫酸化分子的方法将是非常有用的。这项工作提出了将胆固醇与合成的硫酸化GAG模拟物缀合使得能够口服递送的概念。合成了硫酸化GAG模拟物的聚焦文库，发现其在球状体条件下以广泛的效价范围（0.8至46 μM）抑制结直肠癌细胞系的生长。含有胆固醇的特定类似物，单独或与临床使用的药物组合，通过腹膜内以及口服给药表现出明显的体内抗癌潜力，如通过离体三级和四级球体生长、癌症干细胞（CSC）标志物和/或自我更新因子所评估的。总之，高度硫酸化的GAG模拟物的胆固醇衍生化提供了用于工程化口服活性的极好方法。
Sulfated glycosaminoglycans (GAGs), or synthetic mimetics thereof, are not favorably viewed as orally bioavailable drugs owing to their high number of anionic sulfate groups. Devising an approach for oral delivery of such highly sulfated molecules would be very useful. This work presents the concept that conjugating cholesterol to synthetic sulfated GAG mimetics enables oral delivery. A focused library of sulfated GAG mimetics was synthesized and found to inhibit the growth of a colorectal cancer cell line under spheroid conditions with a wide range of potencies ( 0.8 to 46 μM). Specific analogues containing cholesterol, either alone or in combination with clinical utilized drugs, exhibited pronounced in vivo anticancer potential with intraperitoneal as well as oral administration, as assessed by ex vivo tertiary and quaternary spheroid growth, cancer stem cell (CSC) markers, and/or self-renewal factors. Overall, cholesterol derivatization of highly sulfated GAG mimetics affords an excellent approach for engineering oral activity.
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影响因子：
7.3
作者：
Gunnarsson, GT;Desai, UR
通讯作者：
Desai, UR
DOI：
10.1007/978-1-4939-1714-3_7
发表时间：
2015-01-01
期刊：
GLYCOSAMINOGLYCANS: CHEMISTRY AND BIOLOGY
影响因子：
--
作者：
Al-Horani, Rami A.;Karuturi, Rajesh;Desai, Umesh R.
通讯作者：
Desai, Umesh R.
影响因子：
4.7
作者：
Chhabra, Mohit;Wimmer, Norbert;Ferro, Vito
通讯作者：
Ferro, Vito
影响因子：
5.7
作者：
Ishiguro T;Ohata H;Sato A;Yamawaki K;Enomoto T;Okamoto K
通讯作者：
Okamoto K
影响因子：
37.3
作者：
Kanwar SS;Yu Y;Nautiyal J;Patel BB;Majumdar AP
通讯作者：
Majumdar AP