42116-55-2Relevant articles and documents
Cryptophycin-55/52 based antibody-drug conjugates: Synthesis, efficacy, and mode of action studies
Chen, Hao,Fu, Yuyin,Gou, Lantu,Guo, Cuiyu,Jiang, Xiaohua,Kang, Tairan,Lai, Qinhuai,Lai, Weirong,Liao, Wei,Lu, Ying,Peng, Yujia,Tao, Yiran,Wang, Ruixue,Wang, Xin,Wang, Yuxi,Wu, Mengdan,Yang, Jinliang,Yao, Yuqin,Yu, Lin,Zhang, Ruirui,Zhang, Yiwen,Zhang, Zhixiong
, (2020/05/11)
Cryptophycin-52 (CR52), a tubulin inhibitor, exhibits promising antitumor activity in vitro (picomolar level) and in mouse xenograft models. However, the narrow therapeutic window in clinical trials limits its further development. Antibody-drug conjugate (ADC), formed by coupling cytotoxic compound (payload) to an antibody via a linker, can deliver drug to tumor locations in a targeted manner by antibody, enhancing the therapeutic effects and reducing toxic and side effects. In this study, we aim to explore the possibility of CR52-based ADC for tumor targeted therapy. Due to the lack of a coupling site in CR52, its prodrug cryptophycin-55 (CR55) containing a free hydroxyl was synthesized and conjugated to the model antibody trastuzumab (anti-HER2 antibody drug approved by FDA for breast cancer therapy) via the linkers based on Mc-NHS and Mc-Val-Cit-PAB-PNP. The average drug-to-antibody ratios (DARs) of trastuzumab-CR55 conjugates (named T-L1-CR55, T-L2-CR55, and T-L3-CR55) were 3.50, 3.29, and 3.35, respectively. These conjugates exhibited potent cytotoxicity in HER2-positive tumor cell lines with IC50 values at low nanomolar levels (0.58–1.19 nM). Further, they displayed significant antitumor activities at the doses of 10 mg/kg in established ovarian cancer (SKOV3) and gastric cancer (NCI–N87) xenograft models without overt toxicities. Finally, the drug releases were analyzed and the results indicated that T-L3-CR55 was able to effectively release CR55 and further epoxidized to CR52, which may be responsible for its best performance in antitumor activities. In conclusion, our results demonstrated that these conjugates have the potential for tumor targeted therapy, which provides insights to further research the CR55/CR52-based ADC for tumor therapy.
COMPOSITIONS AND METHODS FOR REDUCING TACTILE DYSFUNCTION, ANXIETY, AND SOCIAL IMPAIRMENT
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Page/Page column 57; 58; 64, (2019/12/25)
The present invention features novel peripherally-restricted non-benzodiazipene analogs with reduced blood brain barrier permeability and methods of use thereof for reducing tactile dysfunction, social impairment, and anxiety in a subject diagnosed with A
Solventless mechanosynthesis of N-protected amino esters
Konnert, Laure,Lamaty, Frederic,Martinez, Jean,Colacino, Evelina
, p. 4008 - 4017 (2014/05/20)
Mechanochemical derivatizations of N- or C-protected amino acids were performed in a ball mill under solvent-free conditions. A vibrational ball mill was used for the preparation of N-protected α- and β-amino esters starting from the corresponding N-unmasked precursors via a carbamoylation reaction in the presence of di-tert-butyl dicarbonate (Boc2O), benzyl chloroformate (Z-Cl) or 9-fluorenylmethoxycarbonyl chloroformate (Fmoc-Cl). A planetary ball mill proved to be more suitable for the synthesis of amino esters from N-protected amino acids via a one-pot activation/esterification reaction in the presence of various dialkyl dicarbonates or chloroformates. The spot-to-spot reactions were straightforward, leading to the final products in reduced reaction times with improved yields and simplified work-up procedures.
