Synthesis, antiproliferative evaluation and in silico studies of a novel steroidal spiro morpholinone.

Autor: Cobos-Ontiveros LA; Facultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de Puebla, 72570 Puebla, Puebla, Mexico., Romero-Hernández LL; Facultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de Puebla, 72570 Puebla, Puebla, Mexico. Electronic address: laura.romerohernandez@correo.buap.mx., Mastranzo-Sánchez EB; Facultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de Puebla, 72570 Puebla, Puebla, Mexico., Colín-Lozano B; Facultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de Puebla, 72570 Puebla, Puebla, Mexico., Puerta A; BioLab, Instituto Universitario de Bio-Orgánica 'Antonio González' (IUBO-AG), Universidad de La Laguna, c/ Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain., Padrón JM; BioLab, Instituto Universitario de Bio-Orgánica 'Antonio González' (IUBO-AG), Universidad de La Laguna, c/ Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain., Merino-Montiel P; Facultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de Puebla, 72570 Puebla, Puebla, Mexico. Electronic address: penelope.merino@correo.buap.mx., Vega Baez JL; Facultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de Puebla, 72570 Puebla, Puebla, Mexico., Montiel-Smith S; Facultad de Ciencias Químicas, Ciudad Universitaria, Benemérita Universidad Autónoma de Puebla, 72570 Puebla, Puebla, Mexico.
Jazyk: angličtina
Zdroj: Steroids [Steroids] 2023 Apr; Vol. 192, pp. 109173. Date of Electronic Publication: 2023 Jan 06.
DOI: 10.1016/j.steroids.2023.109173
Abstrakt: Estrogens play a pivotal role in the development of estrogen-dependent breast cancer and other hormone-dependent disorders. A common strategy to overcome the pathological effects of estrogens is the use of aromatase inhibitors (AIs), which bind to the enzyme and prevent the union with the natural substrate, decreasing the amount of estrogens produced. Several AIs have been developed, including inhibitors with a steroidal backbone and a nitrogen heterocycle in their structure. Encouraged by the notable results presented by current and clinical steroidal drugs, herein we present the synthesis of a steroidal spiro morpholinone derivative as a plausible aromatase inhibitor. The morpholinone derivative was synthesized over a six-step methodology starting from estrone. The title compound and its hydroxychloroacetamide derivative precursor were evaluated for their antiproliferative profile against estrogen-dependent and independent solid tumor cell lines: A549, HBL-100, HeLa, SW1573, T-47D and WiDr. Both compounds exhibited a potent antiproliferative activity in the micromolar range against the six cancer cell lines, with the hydroxychloroacetamide derivative precursor being a more potent inhibitor (GI 50  = 0.25-2.4 µM) than the morpholinone derivative (GI 50  = 2.0-11 µM). Furthermore, both compounds showed, in almost all cases, better GI 50 values than the steroidal anticancer drugs abiraterone and galeterone. Docking simulations of the derivatives were performed in order to explain the experimental biological activity. The results showed interactions with the iron heme (derivative 3) and important residues of the steroidal binding-site (Met374) for the inhibition of human aromatase. A correlation was found between in vitro assays and the score obtained from the molecular docking study.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023. Published by Elsevier Inc.)
Databáze: MEDLINE
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