Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Fluorinated Candidates as PI3K Inhibitors: Targeting Fluorophilic Binding Sites

Abstract

Highly fluorinated candidates containing anticancer pharmacophores like thiosemicarbazone (5a–e) and its cyclic analogues hydrazineylidenethiazolidine (6a–e), 2-aminothiadiazole (7a–e), and 2-hydrazineylidenethiazolidin-4-one (8a–e) were synthesized, and their cytotoxic activity was assayed against 60 tumor cell lines. Compounds 6c, 7b, and 8b displayed the most potent activity with lower toxic effects on MCF-10a. In vitro phosphatidylinositol 3-kinase (PI3K) enzyme inhibition was performed. Compound 6c displayed half-maximal inhibitory concentration (IC50, μM) values of 5.8, 2.3, and 7.9; compound 7b displayed IC50 values of 19.4, 30.7, and 73.7; and compound 8b displayed IC50 values of 77.5, 53.5, and 121.3 for PI3Kα, β, and δ, respectively. Moreover, cell cycle progression caused cell cycle arrest at the S phase for compounds 6c and 8b and at G1/S for compound 7b, while apoptosis was induced. In silico studies; molecular docking; physicochemical parameters; and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis were performed. The results showed that compound 6c is the most potent one with a selectivity index (SI) of 39 and is considered as a latent lead for further optimization of anticancer agents.

Steric Blockade of Oxy-Myoglobin Oxidation by Thiosemicarbazones: Structure–Activity Relationships of the Novel PPP4pT Series

“…Thiosemicarbazones remain an intriguing and topical class of anticancer agents that continue to attract considerable attention. ,− The current evaluation of novel PPP4pT analogues included a thorough analysis of structure–activity relationships, revealing a substantial influence of the substituents on electrochemistry and biological efficacy. The correlation between redox potentials and Hammett substituent parameter ( σ p ) demonstrated the significant impact of the substituents through both inductive and resonance effects.…”

Anticancer Activities of Tetrasubstituted Imidazole‐Pyrimidine‐Sulfonamide Hybrids as Inhibitors of EGFR Mutants

“…Cell‐cycle stages were recognized through flow cytometry after PI staining followed by RNase treatment. The MCF‐7 cells were incubated with1 μM of this compound for 24 h, and then its effect on the cell‐cycle profile was analyzed using Flow Cytometry as reported [2,46,47] . MCF‐7 cells were incubated with a vehicle that exhibited normal cell‐cycle phases; moreover 59.05 %, 31.94 %, and 9.01 % of the cells were in the G1, S, and G2 phases, respectively, as in Table 6.…”

“…Among the investigated strategies to control cancer, inhibition of signal transduction pathways was demonstrated as a very effective technique. [2] Of these signal transduction pathways, an epidermal growth factor receptor (EGFR) represents an impactful cancer-fighting intervention methodology. [3][4][5] EGFR is a member of the ErbB family of the receptor tyrosine kinases (RTKs).…”

“…Consequently, controlling malignant tumours is a major focus in health research. Among the investigated strategies to control cancer, inhibition of signal transduction pathways was demonstrated as a very effective technique [2] . Of these signal transduction pathways, an epidermal growth factor receptor (EGFR) represents an impactful cancer‐fighting intervention methodology [3–5] …”

Developing an Anticancer Platinum(II) Compound Based on the Uniqueness of Human Serum Albumin

“…Thiosemicarbazone compounds are promising new anticancer agents and have been widely studied. − Excitingly, several thiosemicarbazone compounds have been simultaneously tested in clinical phase I or II trials. − In addition, other new series of thiosemicarbazone compounds have been developed, which have significant anticancer activity and selectivity, and can overcome the resistance of cancer cells to existing chemotherapy drugs. − At present, there are two main promising approaches for the rational design of anticancer metal agents based on new target(s) or mechanism(s) and the combination of metal ions and ligands with anticancer activity. − Obviously, these pioneering studies offer an innovative possibility to develop new anticancer metal drugs derived from thiosemicarbazone ligands. In fact, metal thiosemicarbazone compounds have not only been widely studied as promising new metal drugs, but they can also kill cancer cells through multiple mechanisms. − …”