Synthesis, inverse docking-assisted identification and in vitro biological characterization of Flavonol-based analogs of fisetin as c-Kit, CDK2 and mTOR inhibitors against melanoma and non-melanoma skin cancers

Identification of potential inhibitors of cutaneous Melanoma and Non-Melanoma skin cancer cells through in-vitro and in-silico screening of a small library of Phenolic compounds

“…The scratch wound healing assay was performed to evaluate compounds 11 or 13 ’s ability to limit the migration and wound closure using a previously described protocol. 25 Briefly, a 24 well plate seeded with cells was incubated until a fully confluent monolayer of cells was scratched a straight line across the center using a sterile 200 µL Gilson pipette tip. Cells were washed gently to remove debris and detached cells and treated with 11 or 13 at escalating concentrations (0, ½IC 50 , IC 50, and 1½IC 50 ).…”

“…From these 10 mM stock solutions, escalating concentrations were prepared using the corresponding cell growth media as a diluent, and the cells (65-75% confluent) were treated with (0-40 µM) or without the drug in sex-to -octuplicate and incubated for 48 h. All treatment protocols and controls were prepared as previously described. 25 The MTT assay method was performed to assess the potency and cytotoxic influence of the test compounds against two cutaneous melanoma (A375 and SK-MEL-28) and two non-melanoma (A431 and SCC-12) skin cancer cell-lines in addition to a control immortalized normal human epidermal keratinocytes (HaCaT) cell line. Briefly, exponentially growing parent passage cells at 70-85% confluency were harvested, washed, counted using a hemocytometer, and individually seeded at a density of 2-5x10 3 Cells/well in a 96 well plate in 200 µL of their respective growth media, incubated and monitored until reaching their log growth phase at over 70% confluent prior to treatment.…”

“…39, 40 We recently showed that fisetin and its analogs inhibit the PI3K/Akt/mTOR and MAPK and effector pathways in organotypic human inflammatory skin and melanoma models, 41, 42 as well as c-Kit, CDK2 and mTOR kinases in melanoma and non-melanoma skin cancers. 25 Herein, we report the in vitro screening of a small library of about 90 compounds previously synthesized in our laboratory against melanoma (A375 and SKMEL-28) and non-melanoma (A431 and SCC-12) skin cancer cell lines. In-silico studies were carried out, aimed at target(s) prediction and at predicting pharmacokinetic and ADMET (absorption, distribution, metabolism, excretion, and toxicity) attributes for selected hit molecules.…”

“…(1H, m), 2.65 -2.68 (5H, m), 3.93 (2H, t, J = 7.2 Hz), 6.50 (1H, d, J = 2.8 Hz), 6.66 (1H, dd, J = 2.8 and 8.8 Hz), 6.78 (2H, d, J = 9.2 Hz), 6.98 (1H, d, J = 8.8 Hz), 7.35 (2H, d, J = keratinocytes ([(absorbance in treatment group/ absorbance in control) x 100%]. GraphPad Prism software version 9.3 (GraphPad Software, Inc., La Jolla, CA, USA) was then used to compute the various IC50 values as earlier described 25.…”

Synthesis of aspirin-curcumin mimic conjugates of potential antitumor and anti-SARS-CoV-2 properties

“…Skin cancers are of two main types, melanoma and non-melanoma (basal and squamous) cell carcinoma. Although the non-melanoma cancers are the more prevalent, melanoma skin cancer is more aggressive with a higher number of deaths [58] .…”