Development of Second-Generation CDK2 Inhibitors for the Prevention of Cisplatin-Induced Hearing Loss.

There are currently no FDA-approved therapies to prevent the hearing loss associated with the usage of cisplatin in chemotherapeutic regimens. We recently demonstrated that the pharmacologic inhibition with kenpaullone or genetic deletion of CDK2 preserved hearing function in animal models treated with cisplatin, which suggests that CDK2 is a promising therapeutic target to prevent cisplatin-induced ototoxicity. In this study, we identified two lead compounds, AT7519 and AZD5438, from a focused library screen of 187 CDK2 inhibitors, performed in an immortalized cell line derived from neonatal mouse cochleae treated with cisplatin.

CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss.

Hearing loss caused by aging, noise, cisplatin toxicity, or other insults affects 360 million people worldwide, but there are no Food and Drug Administration-approved drugs to prevent or treat it. We screened 4,385 small molecules in a cochlear cell line and identified 10 compounds that protected against cisplatin toxicity in mouse cochlear explants. Among them, kenpaullone, an inhibitor of multiple kinases, including cyclin-dependent kinase 2 (CDK2), protected zebrafish lateral-line neuromasts from cisplatin toxicity and, when delivered locally, protected adult mice and rats against cisplatin- and noise-induced hearing loss.

Progress in the Development of Preventative Drugs for Cisplatin-Induced Hearing Loss.

Cisplatin is a highly effective treatment for malignant cancers and has become a cornerstone in chemotherapeutic regimens. Unfortunately, its use in the clinic is often coupled with a high incidence of severe hearing loss. Over the past few decades, enormous effort has been put forth to find protective agents that selectively protect against the ototoxic side effects of cisplatin and do not interfere with its antitumoral activity.

Conversion of Methyl Ketones and Methyl Sulfones into α-Deutero-α,α-Difluoromethyl Ketones and α-Deutero-α,α-Difluoromethyl Sulfones in Three Synthetic Steps.

Deuterodifluoromethyl ketones and sulfones were assembled in three synthetic steps from methyl ketones and sulfones, respectively. The key synthetic transformation is the deuteration of the difluorocarbanion generated by the release of trifluoroacetate from highly α-fluorinated gem-diols. High levels of deuterium on the "CFD" group were routinely observed.

Application of the Pentafluorosulfanyl Group as a Bioisosteric Replacement.

The success of fluorinated molecules in drug design has led medicinal chemists to search for new fluorine-containing substituents. A major recently developed group is the pentafluorosulfanyl group. This group is stable under physiological conditions and displays unique physical and chemical properties.

Generation of Magnesium Pentafluoropropen-2-olate from Hexafluoroisopropanol and Synthesis of 2,2,4,4,4-Pentafluoro-3,3-dihydroxyketones.

2,2,4,4,4-Pentafluoro-3,3-dihydroxyketones are valuable precursors to difluoroenolates following fragmentation during the release of trifluoroacetate; however, there are few synthetic strategies to prepare this unique class of compound. We addressed this issue and report a mild, two-step synthesis of 2,2,4,4,4-pentafluoro-3,3-dihydroxyketones from aldehydes. Specifically, aldehydes are treated with pentafluoropropen-2-olate, generated from a new fragmentation of hexafluoroisopropanol with a mixed Mg/Li amide, to give pentafluoroalcohols.

Optimized Synthesis of a Pentafluoro--diol and Conversion to a -Glucopyranose through Trifluoroacetate-Release and Halogenation.

Pentafluoro--diols are substrates that enable the synthesis of valuable difluoromethylene-containing organic molecules through the release of trifluoroacetate. Currently, only one synthetic strategy is available to assemble these important precursors. Herein, two new synthetic strategies to a complex pentafluoro--diol are compared to the existing route, and an improved synthetic route has completed.

Effect of Substituents and Stability of Transient Aluminum-Aminals in the Presence of Nucleophiles.

Disubstituted hydroxylamines were synthesized and used to form aluminum-amide complexes. These reagents masked carbonyl groups in situ from nucleophilic addition. The stability and utility of the aluminum-aminals are presented in the context of selectively controlling nucleophilic addition on substrates with multiple carbonyl groups.