Novel Active Homo-Aza (Lactam) Steroidal Antimetabolites for the Treatment of Human Pancreatic and Colorectal Cancer
Konstantinos E. Alifieris, Panagiotis Dalezis, Sofia Sagredou, Ioanna A. Anastasiou, Maria Deligiorgi, Christos Siokatas, Nikolaos Spanakis, Konstantinos Almpanakis, Maria Voura, Kyriakos Orfanakos, Mihalis Panayiotidis, Vasiliki Sarli, Dimitrios T. Trafalis
TL;DR
Researchers developed new steroidal drugs that show promise in treating pancreatic and colorectal cancers by targeting specific enzymes and inducing cell death.
Contribution
The study introduces novel lactam steroidal antimetabolites with dual enzyme inhibition and strong preclinical efficacy.
Findings
CS23 showed potent antiproliferative activity and induced apoptosis in cancer cells.
CS23 exhibited high binding affinity for thymidylate synthase and dihydrofolate reductase.
Strong correlations were found between docking scores and biological activity of the compounds.
Abstract
Background: Colorectal and pancreatic cancers remain therapeutically challenging, with limitations in efficacy and limitations due to toxicity from conventional antimetabolites such as 5-fluorouracil (5-FU), methotrexate (MTX), and gemcitabine (GEM). Steroidal conjugation offers an approach to enhance selectivity and toxicokinetics. Methods: Five novel hybrid homo-aza (lactam) steroidal antimetabolites (GE23, CS18, CS23, KA44, MV16) were synthesized and tested against three pancreatic and four colorectal carcinoma cell lines with distinct molecular characteristics. Antiproliferative activity (MTT), apoptosis (Annexin V/PI), and cell cycle effects were assessed. Thymidylate synthase (TS) and dihydrofolate reductase (DHFR) inhibition was examined via molecular docking, Western blot, and enzymatic assays. Correlations between docking binding scores (DBS) and biological data were analyzed,…
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Taxonomy
TopicsColorectal Cancer Treatments and Studies · Estrogen and related hormone effects · Steroid Chemistry and Biochemistry