Disparities in Musculoskeletal Oncology.

PURPOSE OF REVIEW: Disparities within the healthcare system serve as barriers to care that lead to poor outcomes for patients. These healthcare disparities are present in all facets of medicine and extend to musculoskeletal oncology care. There are various tenets to health disparities with some factors being modifiable and non-modifiable. The factors play a direct role in a patient's access to care, time of presentation, poor social determinants of health, outcomes and survival. RECENT FINDINGS: In musculoskeletal oncologic care, factors such as race, socioeconomic factors and insurance status are correlated to advanced disease upon presentation and poor survival for patients with a sarcoma diagnosis. These factors complicate the proper delivery of coordinated care that is required for optimizing patient outcomes. Healthcare disparities lead to suboptimal outcomes for patients who require musculoskeletal oncologic care in the short and long term. More research is required to identify ways to address the known modifiable and non-modifiable factors to improve patient outcome.

Role of the C8 gem-dimethyl group of bryostatin 1 on its unique pattern of biological activity.

The role of the C(8) gem-dimethyl group in the A-ring of bryostatin 1 has been examined through chemical synthesis and biological evaluation of a new analogue. Assays for biological function using U937, K562, and MV4-11 cells as well as the profiles for downregulation of PKC isozymes revealed that the presence of this group is not a critical determinant for the unique pattern of biological activity of bryostatin.

Phase-transfer-catalyzed asymmetric glycolate alkylation.

[reaction: see text] Asymmetric surrogate glycolate alkylation has been performed under phase-transfer conditions. Diphenylmethyloxy-2,5-dimethoxyacetophenone with trifluorobenzyl cinchonidinium catalyst and cesium hydroxide provided alkylation products at -35 degrees C in high yield (80-99%) and with excellent enantioselectivities (90:10 to 95:5). Useful alpha-hydroxy products were obtained using bis-TMS peroxide Baeyer-Villiger conditions and selective transesterification. The intermediate aryl ester can be obtained with >99% ee after a single recrystallization. A tight ion-pair model for the observed (S)-stereoinduction is proposed.

Substitution on the A-ring confers to bryopyran analogues the unique biological activity characteristic of bryostatins and distinct from that of the phorbol esters.

A close structural analogue of bryostatin 1, which differs from bryostatin 1 only by the absence of the C(30) carbomethoxy group (on the C(13) enoate of the B-ring), has been prepared by total synthesis. Biological assays reveal a crucial role for substitution in the bryostatin 1 A-ring in conferring those responses which are characteristic of bryostatin 1 and distinct from those observed with PMA.

Total synthesis of the hydroxyketone kurasoin A using asymmetric phase-transfer alkylation.

The total synthesis of the farnesyltransferase inhibitor kurasoin A has been achieved using a novel asymmetric phase-transfer-catalyzed glycolate alkylation reaction. 2,5-Dimethoxyacetophenone 7 with cinchonidinium catalyst 9(10 mol %) and hydroxide base with pivaloyl benzyl bromide 8 provided S-alkylation product 10 in high yield (80-99%) and excellent enantioselectivity. Baeyer-Villiger oxidation, Weinreb amide formation, and benzyl Grignard addition to the TES-ether 17 gave the protected target. Lithium hydroxide and peroxide generated kurasoin A ([alpha](D) +8.4 degrees ) without isomerization.

Asymmetric phase-transfer catalyzed glycolate alkylation, investigation of the scope, and application to the synthesis of (-)-ragaglitazar.

[Reaction: see text]. Asymmetric glycolate alkylation using a protected acetophenone surrogate under solid-liquid phase-transfer conditions is a new approach to the synthesis of 2-hydroxy esters and acids. Diphenylmethyloxy-2,5-dimethoxyacetophenone 1 with a trifluorobenzyl cinchonidinium bromide catalyst 9 (10 mol %) and cesium hydroxide provided S-alkylation products 2 at -35 degrees C in high yield (80-99%) and with excellent enantioselectivities using a wide range of electrophiles (80-90% ee). Alkylated products were elaborated to useful alpha-hydroxy intermediates 3 using bis-TMS peroxide Baeyer-Villiger conditions and selective transesterification reactions. The ester products have been enantioenriched by simple recrystallization from ether to give a single isomer (99% ee). A tight ion-pair model is proposed for the observed S-stereoinduction that includes van der Waals contacts between the extended enolate and the isoquinoline of the catalyst. To demonstrate the utility of the new methodology, the anti-diabetes drug (-)-ragaglitazar 24 was synthesized in six steps from a key 2-alkoxy-3-p-phenoxypropionic acid 26 that was made using PTC glycolate alkylation.