Structure modification: a successful tool for prodrug design.

Prodrug strategy is critical for innovative drug development. Structural modification is the most straightforward and effective method to develop prodrugs. Improving drug defects and optimizing the physical and chemical properties of a drug, such as lipophilicity and water solubility, changing the way of administration can be achieved through specific structural modification. Designing prodrugs by linking microenvironment-responsive groups to the prototype drugs is of great help in enhancing drug targeting. In the meantime, making connections between prodrugs and suitable drug delivery systems could realize drug loading increases, greater stability, bioavailability and drug release control. In this paper, lipidic, water-soluble, pH-responsive, redox-sensitive and enzyme-activatable prodrugs are reviewed on the basis of structural modification.

Synthesis of Aryldiphenylphosphine Oxides by Quaternization of Tertiary Diphenylphosphines with Aryl Bromides Followed by the Wittig Reaction.

A two-step method for the synthesis of aryldiphenylphosphine oxides from tertiary diphenylphosphines and aryl bromides is developed. The first step is the quaternization of methyldiphenylphosphine or benzyldiphenylphosphine with aryl bromides. This quaternization can be nickel-catalyzed (metal-free in some cases), and tolerate of a variety of functional groups, furnishing quaternary phosphonium salts in 48-90% yields. The second step is Wittig reactions of these quaternary phosphonium salts with furan-2-carbaldehyde or p-chlorobenzaldehyde to provide aryldiphenylphosphine oxides in 27-90% yields. The use of the Wittig reaction for the synthesis of tertiary phosphine oxides is in contrast to its traditional use for the synthesis of olefins, leaving tertiary phosphine oxide as a byproduct. This quaternization-Wittig method can be applied to synthesize aryldiphenylphosphine oxides that are difficult to access by the alkaline hydrolysis of aryltriphenylphosphonium salts, especially those bearing an electron-deficient aryl group. The ligand-coupling mechanism for the alkaline hydrolysis of (p-acylphenyl)triphenylphosphonim salts is also discussed.

Development and validation of a prognostic model for kidney renal clear cell carcinoma based on RNA binding protein expression.

Dysregulated expression of RNA-binding proteins (RBPs) is strongly associated with the development and progression of multiple tumors. However, little is known about the role of RBPs in kidney renal clear cell carcinoma (KIRC). In this study, we examined RBP expression profiles using The Cancer Genome Atlas database and identified 133 RBPs that were differentially expressed in KIRC and non-tumor tissues. We then systematically analyzed the potential biological functions of these RBPs and established PPIs. Based on Lasso regression and Cox survival analyses, we constructed a risk model that could independently and accurately predict prognosis based on seven RBPs (NOL12, PABPC1L, RNASE2, RPL22L1, RBM47, OASL, and YBX3). Survival times were shorter in patients with high risk scores for cohorts stratified by different characteristics. Gene set enrichment analysis was also performed to further understand functional differences between high- and low-risk groups. Finally, we developed a clinical nomogram with a concordance index of 0.792 for estimating 3- and 5-year survival probabilities. Our results demonstrate that this risk model could potentially improve individualized diagnostic and therapeutic strategies.

Metal-Free Synthesis of Aryltriphenylphosphonium Bromides by the Reaction of Triphenylphosphine with Aryl Bromides in Refluxing Phenol.

A metal-free synthesis of aryltriphenylphosphonium bromides by the reaction of triphenylphosphine with aryl bromides in refluxing phenol is developed. This reaction tolerates hydroxymethyl, hydroxyphenyl, and carboxyl groups in aryl bromides, allowing to synthesize multifunctional aryltriphenylphosphonium bromides, from which facile access to multifunctional aryldiphenylphosphines and their oxides by hydrolysis and subsequent reduction is exemplified. A two-step addition-elimination mechanism, with the elimination step being a fast step, is also proposed.