A gulose moiety contributes to the belomycin (BLM) disaccharide selective targeting to lung cancer cells

  • Eur J Med Chem. 2021 Dec 15:226:113866. doi: 10.1016/j.ejmech.2021.113866.
Cui Zhou  1 ,  Wenchong Ye  1 ,  Yongjun Cao  2 ,  Meizhu Wang  1 ,  Dongxia Qi  3 ,  Guohao Liao  4 ,  Houkai Li  5 ,  Weiping Huang  4 ,  Wenming Chen  6 ,  Xiaoyang Wang  7 ,  Wen Zhou  8
Affiliations
  • 1. School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, University Town, Waihuan Rd, Panyu, Guangzhou, 510006, China; Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China.
  • 2. Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, 510120, Guangdong, China.
  • 3. Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China.
  • 4. School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, University Town, Waihuan Rd, Panyu, Guangzhou, 510006, China.
  • 5. Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 6. Department of Pharmaceutical Production Center＆TCM and Ethnomedicine Development International Laboratory, The First Hospital of Hunan University of Chinese Medicine, 95, Shaoshan Rd, Changsha, Hunan, 41007, China. Electronic address: [email protected].
  • 7. Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China; Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241, PR China. Electronic address: [email protected].
  • 8. Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China; Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241, PR China. Electronic address: [email protected].
PMID: 34619466 DOI: 10.1016/j.ejmech.2021.113866
Abstract

Eight mono- or disaccharide analogues derived from BLM disaccharide, along with the corresponding carbohydate-dye conjugates have been designed and synthesized in this study, aiming at exploring the effect of a gulose residue on the cellular binding/uptake of BLM disaccharide and it possible uptake mechanism. Our evidence is presented indicating that, for the cellular binding/uptake of BLM disaccharide, a gulose residue is an essential subunit but unrelated to its chemical nature. Interestingly, d-gulose-dye conjugate is able to selectively target A549 Cancer cells, but l-gulose-dye conjugate fails. Further uptake mechanism studies demonstrate d-gulose-dye derivatives similar to BLM disaccharide-dye ones behave in a temperature- and ATP-dependent manner, and are partly directed by the GLUT1 receptor. Moreover, d-gulose modifying gemcitabine 53a exhibits more potent antitumor activity compared to derivatives 53b-c in which gemcitabine is decorated with other Monosaccharides. Taken together, the monosacharide d-gulose conjugate offers a new strategy for solving cytotoxic drugs via the increased tumor targeting in the therapy of lung Cancer.

Keywords
BLM disaccharide; Gulose; Imaging study; SAR; Selective uptake mechanism.