Cosmeceutical formulations of pro-vitamin E phosphate: In-vitro release testing and dermal penetration into excised human skin.

Long-term exposure to solar radiation can lead to skin damage such as photoageing, and photocarcinogenesis. This can be prevented by topically applying α-tocopherol phosphate (α-TP). The major challenge is that a significant amount of α-TP needs to reach viable skin layers for effective photoprotection. This study aims to develop candidate formulations of α-TP (gel-like, solution, lotion, and gel), and investigate formulation characteristics' effect on membrane diffusion and human skin permeation. All the formulations developed in the study had an appealing appearance and no signs of separation. All formulations had low viscosity and high spreadability except the gel. The flux of α-TP through the polyethersulfone membrane was the highest for lotion (6.63 ±â€¯0.86 mg/cm2/h), followed by control gel-like (6.14 ±â€¯1.76 mg/cm2/h), solution (4.65 ±â€¯0.86 mg/cm2/h), and gel (1.02 ±â€¯0.22 mg/cm2/h). The flux of α-TP through the human skin membrane was numerically higher for lotion compared to the gel-like (328.6 vs.175.2 µg/cm2/h). The lotion delivered 3-fold and 5-fold higher α-TP in viable skin layers at 3 h and 24 h, respectively, compared to that of the gel-like. The low skin membrane penetration rate and deposition of α-TP in viable skin layers were observed for the solution and gel. Our study demonstrated that dermal penetration of α-TP was influenced by characteristics of formulation such as formulation type, pH, and viscosity. The α-TP in the lotion scavenged higher DPPH free radicals compared to that of gel-like (almost 73% vs. 46%). The IC50 of α-TP in lotion was significantly lower than that of gel-like (397.2 vs. 626.0 µg/mL). The preservative challenge test specifications were fulfilled by Geogard 221 and suggested that the combination of benzyl alcohol and Dehydroacetic Acid effectively preserved 2% α-TP lotion. This result confirms the suitability of the α-TP cosmeceutical lotion formulation employed in the present work for effective photoprotection.

Kinesin spindle protein inhibitors in cancer: from high throughput screening to novel therapeutic strategies.

Bringing to a halt the cell cycle in mitosis and interfering with its normal progression is one of the most successful anti-cancer strategies used nowadays. Classically, several kinds of anti-cancer drugs like taxanes and vinca alkaloids directly inhibit microtubules during cell division. These drugs exhibit serious side effects, most importantly, severe peripheral neuropathies. Alternatively, KSP inhibitors are grasping a lot of research attention as less toxic mitotic inhibitors. In this review, we track the medicinal chemistry developmental stages of KSP inhibitors. Moreover, we address the challenges that are faced during the development of KSP inhibitor therapy for cancer and future insights for the latest advances in research that are directed to find active KSP inhibitor drugs.

QSAR-guided pharmacophoric modeling reveals important structural requirements for Polo kinase 1 (Plk1) inhibitors.

Targeting Polo-like kinase 1 (Plk1) by molecular inhibitors is being a promising approach for tumor therapy. Nevertheless, insufficient methodical analyses have been done to characterize the interactions inside the Plk1 binding pocket. In this study, an extensive combined ligand and structure-based drug design workflow was conducted to data-mine the structural requirements for Plk1 inhibition. Consequently, the binding modes of 368 previously known Plk1 inhibitors were investigated by pharmacophore generation technique. The resulted pharmacophores were engaged in the context of Genetic function algorithm (GFA) and Multiple linear regression (MLR) analyses to search for a prognostic QSAR model. The most successful QSAR model was with statistical criteria of (r2277 = 0.76, r2adj = 0.76, r2pred = 0.75, Q2 = 0.73). Our QSAR-selected pharmacophores were validated by Receiver Operating Characteristic (ROC) curve analysis. Later on, the best QSAR model and its associated pharmacophoric hypotheses (HypoB-T4-5, HypoI-T2-7, HypoD-T4-3, and HypoC-T3-3) were used to identify new Plk1 inhibitory hits retrieved from the National Cancer Institute (NCI) database. The most potent hits exhibited experimental anti-Plk1 IC50 of 1.49, 3.79. 5.26 and 6.35 µM. Noticeably, our hits, were found to interact with the Plk1 kinase domain through some important amino acid residues namely, Cys67, Lys82, Cys133, Phe183, and Asp194.