Advancements in sunscreen formulations: integrating polyphenolic nanocarriers and nanotechnology for enhanced UV protection.

Sunscreens are essential in protecting the skin from harmful effects of ultraviolet radiation (UVR). These formulations, designed to absorb, block, or scatter UVR, offer vital protection against skin aging, sunburns, and the development of skin cancers like melanomas. However, some sunscreens, especially those containing organic/chemical compounds, can cause allergic reactions. To address this, researchers are extensively investigating formulations that incorporate plant extracts rich in polyphenols, such as flavonoids and carotenoids, which can be considered safer alternatives. Products derived from plants are commonly used in cosmetics to counteract skin aging due to their antioxidant activity that combat harmful free radicals. This review focuses on evaluating the advancements in chemical and natural sunscreens, exploring the integration of polyphenolic nanocarriers within sunscreen formulas, their interaction with UVR, and utilizing nanotechnology to enhance their effectiveness. An attempt has been made to highlight the concerns related to toxicity associated with their use and notable advancements in the regulatory aspects governing their utilization.

Development of a Series of Pyrrolopyridone MAT2A Inhibitors.

The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ'9567 (21), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro and in vivo, providing further evidence to support the utility of MAT2a inhibitors as potential anticancer therapies for MTAP-deficient tumors.

Discovery and In Vivo Efficacy of AZ-PRMT5i-1, a Novel PRMT5 Inhibitor with High MTA Cooperativity.

PRMT5, a type 2 arginine methyltransferase, has a critical role in regulating cell growth and survival in cancer. With the aim of developing MTA-cooperative PRMT5 inhibitors suitable for MTAP-deficient cancers, herein we report our efforts to develop novel "MTA-cooperative" compounds identified through a high-throughput biochemical screening approach. Optimization of hits was achieved through structure-based design with a focus on improvement of oral drug-like properties. Bioisosteric replacement of the original thiazole guanidine headgroup, spirocyclization of the isoindolinone amide scaffold to both configurationally and conformationally lock the bioactive form, and fine-tuning of the potency, MTA cooperativity, and DMPK properties through specific substitutions of the azaindole headgroup were conducted. We have identified an orally available in vivo lead compound, 28 ("AZ-PRMT5i-1"), which shows sub-10 nM PRMT5 cell potency, >50-fold MTA cooperativity, suitable DMPK properties for oral dosing, and significant PRMT5-driven in vivo efficacy in several MTAP-deficient preclinical cancer models.