2. Academic Validation
  3. Heterocycle-functional steroidal derivatives: Design, synthesis, bioevaluation and SARs of steroidal pyrazolo[1,5-a]pyrimidines as potential ALK inhibitors

Heterocycle-functional steroidal derivatives: Design, synthesis, bioevaluation and SARs of steroidal pyrazolo[1,5-a]pyrimidines as potential ALK inhibitors

  • Bioorg Chem. 2024 Sep 27:153:107847. doi: 10.1016/j.bioorg.2024.107847.
Fang Liu 1,  Shaohua Wen 1,  Manli Liu 1,  Yong Min 1,  Zhigang Zhang 1,  Liqiao Shi 1,  Kaimei Wang 1,  Yunxia Deng 2,  Ziwen Yang 3,  Fei Yang 4,  Shaoyong Ke 5
Affiliations

Affiliations

  • 1 Key Laboratory of Microbial Pesticides, Ministry of Agriculture and Rural Affairs, National Biopesticide Engineering Research Centre, Hubei Biopesticide Engineering Research Centre, Hubei Academy of Agricultural Sciences, Wuhan 430064, China.
  • 2 Guangdong Jiangmen Chinese Medicine College, Jiangmen 529000, China.
  • 3 Key Laboratory of Microbial Pesticides, Ministry of Agriculture and Rural Affairs, National Biopesticide Engineering Research Centre, Hubei Biopesticide Engineering Research Centre, Hubei Academy of Agricultural Sciences, Wuhan 430064, China; College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 4 Key Laboratory of Microbial Pesticides, Ministry of Agriculture and Rural Affairs, National Biopesticide Engineering Research Centre, Hubei Biopesticide Engineering Research Centre, Hubei Academy of Agricultural Sciences, Wuhan 430064, China; Guangdong Jiangmen Chinese Medicine College, Jiangmen 529000, China; College of Life Sciences, Wuhan University, Wuhan 430072, China. Electronic address: feiy_2017@whu.edu.cn.
  • 5 Key Laboratory of Microbial Pesticides, Ministry of Agriculture and Rural Affairs, National Biopesticide Engineering Research Centre, Hubei Biopesticide Engineering Research Centre, Hubei Academy of Agricultural Sciences, Wuhan 430064, China. Electronic address: shaoyong.ke@nberc.com.
PMID: 39348750 DOI: 10.1016/j.bioorg.2024.107847
Abstract

Two series of heterocyclic steroidal pyrazolo[1,5-a]pyrimidines derived from dehydroepiandrosterone (DHEA) and epiandrosterone (EPIA) were designed and synthesized, and these compounds were screened for their potential antiproliferation activities. The preliminary bioassay indicated that some of target compounds exhibited significantly good antiproliferation activities against human melanoma cell line (A875) and human hepatocellular carcinoma (Huh-7) cell lines compared with 5-fluorouracil (5-FU), and some of which present good antiproliferative activities as potential ALK inhibitors. The detailed analysis of structure-activity relationships (SARs) based on the inhibition activities, kinase assay, and molecular docking demonstrated that the antiproliferation activities of these steroidal pyrazolo[1,5-a]pyrimidine might be affected by the β-hydroxyl group of steroidal scaffold and the N atom of pyridine heterocycle. Especially, compound 4c has certain inhibitory effects on the tyrosine protein kinases ALK, CDK2/CyclinE1, FAK, CDK5/P35, CDK9/CyclinT1, CDK5/P25, PIM2, CDK2/CyclinA2, CDK1/CyclinB1, etc., and which displayed highest inhibitory effect on the kinases of ALK with inhibition rate 40.63 % at the concentration of 10 μM, which induced cell death in A875 cells at least partly (initially), by Apoptosis.

Keywords

Anaplastic lymphoma kinase; Antiproliferation; Dehydroepiandrosterone; Epiandrosterone; Steroidal pyrazolo[1,5-a]pyrimidine; Structure-activity relationships.

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