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Volume 16
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10.3390/ph16020209
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Article

Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues

by
Caroline Marques Xavier Costa
1,2,†,
Cristiane Aparecida-Silva
1,2,†,
Luis Eduardo Reina Gamba
1,2,
Thalita Neves de Melo
1,2,
Gisele Barbosa
1,2,*,
Manoel Oliveira de Moraes Junior
1,2,
Victoria Regina Thomaz de Oliveira
1,2,
Carolinne Souza de Amorim
3,
João A. Moraes
3,
Eliezer Jesus Barreiro
1,2 and
Lídia Moreira Lima
1,2,*
1
Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio®), Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, CCS, Cidade Universitária, Rio de Janeiro 21941-971, RJ, Brazil
2
Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-909, RJ, Brazil
3
Laboratório de Biologia Redox (LABIO-RedOx®), Instituto de Ciências Biológicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Pharmaceuticals 2023, 16(2), 209; https://doi.org/10.3390/ph16020209
Submission received: 30 December 2022 / Revised: 20 January 2023 / Accepted: 25 January 2023 / Published: 30 January 2023
(This article belongs to the Section Medicinal Chemistry)
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Abstract

Targeted antitumour therapy has revolutionized the treatment of several types of tumours. Among the validated targets, phosphatidylinositol-3 kinase (PI3K) deserves to be highlighted. Several PI3K inhibitors have been developed for the treatment of cancer, including gedatolisib (4). This inhibitor was elected as a prototype and molecular modifications were planned to design a new series of simplified gedatolisib analogues (5a-f). The analogues were synthesised, and the comparative cytotoxic activity profile was studied in phenotypic models employing solid and nonadherent tumour cell lines. Compound 5f (LASSBio-2252) stood out as the most promising of the series, showing good aqueous solubility (42.38 μM (pH = 7.4); 39.33 μM (pH = 5.8)), good partition coefficient (cLogP = 2.96), cytotoxic activity on human leukemia cell lines (CCRF-CEM, K562 and MOLT-4) and an excellent metabolic stability profile in rat liver microsomes (t1/2 = 462 min; Clapp = 0.058 mL/min/g). The ability of 5f to exert its cytotoxic effect through modulation of the PI3K pathway was demonstrated by flow cytometry analysis in a comparative manner to gedatolisib.
Keywords: cancer; PI3K inhibitors; gedatolisib; flow cytometry; MTT cancer; PI3K inhibitors; gedatolisib; flow cytometry; MTT
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MDPI and ACS Style

Costa, C.M.X.; Aparecida-Silva, C.; Gamba, L.E.R.; de Melo, T.N.; Barbosa, G.; Moraes Junior, M.O.d.; de Oliveira, V.R.T.; de Amorim, C.S.; Moraes, J.A.; Barreiro, E.J.; et al. Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues. Pharmaceuticals 2023, 16, 209. https://doi.org/10.3390/ph16020209

AMA Style

Costa CMX, Aparecida-Silva C, Gamba LER, de Melo TN, Barbosa G, Moraes Junior MOd, de Oliveira VRT, de Amorim CS, Moraes JA, Barreiro EJ, et al. Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues. Pharmaceuticals. 2023; 16(2):209. https://doi.org/10.3390/ph16020209

Chicago/Turabian Style

Costa, Caroline Marques Xavier, Cristiane Aparecida-Silva, Luis Eduardo Reina Gamba, Thalita Neves de Melo, Gisele Barbosa, Manoel Oliveira de Moraes Junior, Victoria Regina Thomaz de Oliveira, Carolinne Souza de Amorim, João A. Moraes, Eliezer Jesus Barreiro, and et al. 2023. "Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues" Pharmaceuticals 16, no. 2: 209. https://doi.org/10.3390/ph16020209

APA Style

Costa, C. M. X., Aparecida-Silva, C., Gamba, L. E. R., de Melo, T. N., Barbosa, G., Moraes Junior, M. O. d., de Oliveira, V. R. T., de Amorim, C. S., Moraes, J. A., Barreiro, E. J., & Lima, L. M. (2023). Design, Synthesis and Phenotypic Profiling of Simplified Gedatolisib Analogues. Pharmaceuticals, 16(2), 209. https://doi.org/10.3390/ph16020209

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