A novel series of pyrimido[5,4-c]quinoline derivatives variously substituted at positions 2 and 5 have been
synthesized, in good to excellent yields, via rapid base-catalyzed cyclization reaction of 2,4-dichloroquinoline-3-
carbonitrile (5) with guanidine hydrochlorides 6a-c. All the synthesized compounds were screened for their in
vitro antiproliferative activity. The most active hybrids 26a-d, 28a-d, and 30B were assessed against topoisomerase
(topo) I, topo IIα, CDK2, and EGFR. The majority of the tested compounds exhibited selective topo I
inhibitory activity while had weak topo IIα inhibitory action with compounds 30B and 28d, showed better topo I
inhibitory activity than the reference camptothecin. Compound 30B, the most potent derivative as antiproliferative
agent, exhibited moderate activity against CDK2 (IC50 = 1.60 μM). The results of this assay show
that CDK2 is not a potential target for these compounds, implying that the observed cytotoxicity of these
compounds is due to a different mechanism. Compounds 30B, 28d, and 28c were found to be the most potent
against EGFR and their EGFR inhibitory activities (IC50 = 0.40 ± 0.2, 0.49 ± 0.2, and 0.64 ± 0.3, respectively)
relative to the positive control erlotinib (IC50 = 0.07 ± 0.03 μM). These results revealed that topo I and EGFR are
attractive targets for this class of chemical compound

Using a single drug to treat cancer with dual-targeting is an unusual approach when compared to other drug
combinations. Dual-targeting agents were developed as a result of insufficient efficacy and drug resistance when
single-targeting agents were used. As a result, the 2,3-dihydropyrazino[1,2-a]indole-1,4-dione derivatives 13–22
have been developed as dual EGFR and BRAFV600E inhibitors. The target compounds were synthesized and tested in vitro against four cancer cell lines, with compounds 15, and 19–22 demonstrating potent antiproliferative
activity. In vitro studies revealed that these compounds have dual inhibitory effect on EGFR and BRAFV600E.
Compounds 15, and 19–22 exhibited inhibitions of EGFR with IC50 ranging from 32 nM to 63 nM which were
superior to erlotinib (IC50 = 80 ± 10 nM). Compounds 20, 21 and 22 showed promising inhibitory activity of
BRAFV600E (IC50 = 55, 45 and 51 nM, respectively) and were found to be potent inhibitors of cancer cell proliferation (GI50 = 51, 35 and 44 nM, respectively). Compounds 20, 21 and 22 showed good antioxidant activity
comparable to the reference Trolox. Lastly, the best active dual inhibitors were docked inside EGFR and
BRAFV600E active sites to clarify their binding modes.

A new series of quinazoline-4-one/chalcone hybrids, 7–26 , was synthesized in this study as EGFR in- hibitors with antiproliferative activity. Target compounds were synthesized and in vitro tested against different cancer cell lines, EGFR, and BRAF enzymes. Three compounds showed the greatest antiprolif- erative activity and were the most potent EGFR inhibitors. Also, these three compounds improved the level of active caspase-3, 8, and 9 with potent induction of cytochrome c and Bax levels, as well as down regulation of Bcl - 2 levels. Finally, the most active inhibitors docked well inside EGFR active sites.

Recent studies have shown that combining kinase inhibitors has additive and synergistic effects. BRAF V600E and p38 αhave been extensively studied as potential therapeutic targets for a variety of dis- eases. In keeping with our interest in developing multi-targeted anticancer agents, a series of novel triaryl-imidazole-based analogues containing 3-aryl-1,2,4-oxadiazoles moiety ( 4a-h , Scaffold B) and their reaction intermediates aryl carboximidamides moiety ( 3a-h, Scaffold A) have been rationally designed, synthesized, and evaluated in vitro for their antiproliferative activity as dual p38 α/BRAF V600E inhibitors. The results revealed that the presence of the carboximidamide moiety is required for activity, and the best activity correlates with the Ar = 1,2-benzodioxole ( 3e ) ≥4-CH 3 O-C 6 H 5 -( 3c ) > 2-naphthyl (3h) > 4-Cl-C 6 H 5 ( 3b ). Ring closure of carboximidamide to 1,2,4-oxadiazole significantly reduces the activity. The results of docking study into p38 αrevealed higher binding affinities for compounds 3c, 3e , and 3h compared to the co-crystallized ligand, SB2. However, the docking study of compounds 3c and 3e into BRAF V600E revealed slightly lower affinities than vemurafenib.

Abstract: The topical delivery of therapeutics is a promising strategy for managing skin conditions. Cyclooxygenase-2 (COX-2) inhibitors showed a possible target for chemoprevention and cancer management. Celecoxib (CXB) is a selective COX-2 inhibitor that impedes cell growth and generates apoptosis in different cell tumors. Herein, an investigation proceeded to explore the usefulness of nano lipid vesicles (transethosomes) (TES) of CXB to permit penetration of considerable quantities of the drug for curing skin cancer. The prepared nanovesicles were distinguished for drug
encapsulation efficiency, vesicle size, PDI, surface charge, and morphology. In addition, FT-IR and DSC analyses were also conducted to examine the influence of vesicle components. The optimized formulation was dispersed in various hydrogel bases. Furthermore, in vitro CXB release and ex vivo permeability studies were evaluated. A cytotoxicity study proceeded using A431 and BJ1 cell lines. The expression alteration of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene and DNA damage and fragmentation using qRT-PCR and comet assays were also investigated. Optimized
CXB-TES formulation was spherically shaped and displayed a vesicle size of 75.9 ± 11.4 nm, a surface charge of - 44.7 ± 1.52 mV, and an entrapment efficiency of 88.8 ± 7.2%. The formulated TES-based hydrogel displayed a sustained in vitro CXB release pattern for 24 h with an enhanced flux and permeation across rat skin compared with the control (free drug-loaded hydrogel). Interestingly, CXB-TES hydrogel has a lower cytotoxic effect on normal skin cells compared with TES suspension and CXB powder. Moreover, the level of expression of the CDKN2A gene was significantly (p ≤ 0.01, ANOVA/Tukey) decreased in skin tumor cell lines compared with normal skin cell lines, indicating that TES are the suitable carrier for topical delivery of CXB to the cancer cells suppressing their progression. In addition, apoptosis demonstrated by comet and DNA fragmentation assays was evident in skin cancer cells exposed to CXB-loaded TES hydrogel formulation. In conclusion, our results illustrate that CXB-TES-loaded hydrogel could be considered a promising carrier and effective chemotherapeutic agent for the management of skin carcinoma.

Herein, we report a facile preparation of vertically oriented reduced graphene oxide sheets (VrGO) supported on
a palladium nanoparticles-decorated graphite electrode. The electrode is fabricated by a simple two electrodeposition steps method. The designed electrode BEFD&VrGO@PdNPs successfully provides an open structure of rGO layer exposing palladium nanoparticles (PdNPs) to the solution, leading to formation of a uniform distributed vertically oriented rGO (VrGO) due to the high surface area of palladium-decorated PGE substrate. The fabricated electrode was successfully used for determination of sorafenib (SOR); an anti-cancer drug. Using square wave voltammetric method (SWV), the fabricated electrochemical sensor succeeds to monitor the electro-oxidation of SOR with a low limit of detection of 9.9 x10? 10 M and ultrahigh sensitivity of 237 μA nM? 1cm? 2 over a linear concentration range of 3–120 10? 9 M with an excellent correlation coefficient. Additionally, the performance of the modified electrode has been successfully tested by real-time monitoring of SOR in pharmaceutical tablets, human plasma, and human urine without any interference from complex matrices.