2. Academic Validation
  3. Bioreductively Activatable Prodrug Conjugates of Combretastatin A-1 and Combretastatin A-4 as Anticancer Agents Targeted toward Tumor-Associated Hypoxia

Bioreductively Activatable Prodrug Conjugates of Combretastatin A-1 and Combretastatin A-4 as Anticancer Agents Targeted toward Tumor-Associated Hypoxia

  • J Nat Prod. 2020 Apr 24;83(4):937-954. doi: 10.1021/acs.jnatprod.9b00773.
Blake A Winn 1,  Laxman Devkota 1,  Bunnarack Kuch 1,  Matthew T MacDonough 1,  Tracy E Strecker 1,  Yifan Wang 1,  Zhe Shi 1,  Jeni L Gerberich 2,  Deboprosad Mondal 1,  Alejandro J Ramirez 3,  Ernest Hamel 4,  David J Chaplin 1 5,  Peter Davis 5,  Ralph P Mason 2,  Mary Lynn Trawick 1,  Kevin G Pinney 1
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, Baylor University, One Bear Place #97348, Waco, Texas 76798-7348, United States.
  • 2 Predictive Imaging Research Laboratory, Department of Radiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9058, United States.
  • 3 Mass Spectrometry Center, Baylor University, One Bear Place #97046, Waco, Texas 76798-7046, United States.
  • 4 Screening Technologies Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, Maryland 21702, United States.
  • 5 Fast Biopharma Ltd., 10 Aston Park, Aston Rowant, OX49 5SW, United Kingdom.
PMID: 32196334 DOI: 10.1021/acs.jnatprod.9b00773
Abstract

The Natural Products combretastatin A-1 (CA1) and combretastatin A-4 (CA4) function as potent inhibitors of tubulin polymerization and as selective vascular disrupting agents (VDAs) in tumors. Bioreductively activatable prodrug conjugates (BAPCs) can enhance selectivity by serving as substrates for reductase Enzymes specifically in hypoxic regions of tumors. A series of CA1-BAPCs incorporating nor-methyl, mono-methyl, and gem-dimethyl nitrothiophene triggers were synthesized together with corresponding CA4-BAPCs, previously reported by Davis (Mol. Cancer Ther. 2006, 5 (11), 2886), for comparison. The CA4-gem-dimethylnitrothiophene BAPC 45 proved exemplary in comparison to its nor-methyl 43 and mono-methyl 44 congeners. It was stable in phosphate buffer (pH 7.4, 24 h), was cleaved (25%, 90 min) by NADPH-cytochrome P450 oxidoreductase (POR), was inactive (desirable prodrug attribute) as an inhibitor of tubulin polymerization (IC50 > 20 μM), and demonstrated hypoxia-selective activation in the A549 cell line [hypoxia cytotoxicity ratio (HCR) = 41.5]. The related CA1-gem-dimethylnitrothiophene BAPC 41 was also promising (HCR = 12.5) with complete cleavage (90 min) upon treatment with POR. In a preliminary in vivo dynamic bioluminescence imaging study, BAPC 45 (180 mg/kg, IP) induced a decrease (within 4 h) in light emission in a 4T1 syngeneic mouse breast tumor model, implying activation and vascular disruption.

Figures