Polymer-supported Schiff base complexes in oxidation reactions

Covering: July 1998 to the end of July 1999. Previous review: J. Chem. Soc., Perkin Trans. 1, 1999, 641.

The synthesis of thiols, selenols, sulfides, selenides, sulfoxides, selenoxides, sulfones and selenones

Hsp90 is a chaperone protein with important roles in maintaining transformation and in elevating the survival and growth potential of cancer cells. Currently there is an increasing interest in developing inhibitors of this protein as anticancer therapeutics. One of such inhibitors, the purine-scaffold class, has been reported to be potent and selective against Hsp90 both in vitro and in vivo models of cancer. Here, a series of 8-arylsulfanyl, -sulfoxyl, and -sulfonyl adenine members of the purine class was synthesized and evaluated as inhibitors of the chaperone. The structure-activity relationship and selectivity for tumor Hsp90 of compounds within the series is presented. Our results suggest that 8-arylsulfanyl adenine derivatives are good inhibitors of chaperone activity, whereas oxidation of the sulfides to sulfoxides or sulfones leads to compounds of decreased activity. The study identifies derivative 11v as the most potent Hsp90 inhibitor of the purine-scaffold series published to date (EC(50) = 30 nM), and also as the compound of this class with highest selectivity for tumor vs normal cell Hsp90 (700 to 3000-fold). Most rewardingly, this work has allowed for the identification of Hsp90 inhibitors with selective affinities for Hsp90-client protein complexes, derivatives that may represent useful pharmacological tools in dissecting Hsp90-regulated processes.

Evaluation of 8-arylsulfanyl, 8-arylsulfoxyl, and 8-arylsulfonyl adenine derivatives as inhibitors of the heat shock protein 90.

Electronic structure of active sites plays a crucial role in redox catalysts. Herein, graphitic carbon nitride (g-C3N4) decorated with metallic MoO2 heterojunction nanocomposites were successfully synthesized through a facile calcination route. XPS, UPS, UV–vis and PL spectra results suggest electron transfer from the conduction band (CB) of g-C3N4 to unfilled π* band of metallic MoO2 in the metal-semiconductor heterojunction. The electron transfer ensures high intrinsic oxidative desulfurization activity for MoO2/g-C3N4 composites. Radical scavenger experiments indicate that the electron transfer facilitates the enrichment of electron density around Mo active sites and control the rate-determining step of oxidative desulfurization. The approach can be extended to other low valent transition metal oxides possessing d electrons for enhanced catalytic activity in redox reactions.

Electronic structure of heterojunction MoO2/g-C3N4 catalyst for oxidative desulfurization

Green oxidations. The use of potassium permanganate supported on manganese dioxide

Silica gel and alumina have been found to mediate the oxidation of sulfides and sulfoxides with (CH3)3COOH and OXONE. With all combinations except (CH3)3COOH/alumina, sulfides were oxidized with reasonably good selectivity to sulfoxides. These studies afforded insights into the mechanisms of surface-mediated processes. Adsorption studies, combined with the effect of partial silylation of silica gel, indicate that oxidation of sulfides by (CH3)3COOH/silica gel occurs at least predominantly via nucleophilic attack by the sulfide on (CH3)3COOH, which is activated by being bound to isolated silanol sites on the silica gel surface (Scheme 2), whereas oxidation of sulfoxides involves nucleophilic attack by (CH3)3COOH on the sulfoxide, which is activated by being bound to associated silanol sites (Scheme 3). Oxidation of sulfoxides by (CH3)3COOH/alumina involves attack of (CH3)3COO- on the sulfoxide bound to free Al+ sites on the surface (Scheme 4B). Mediation of oxidation by OXONE involves instead activation by...

Surface-Mediated Reactions. 8. Oxidation of Sulfides and Sulfoxides with tert-Butyl Hydroperoxide and OXONE1

Surface-Mediated Reactions. Part 8. Oxidation of Sulfides and Sulfoxides with tert-Butyl Hydroperoxide and OXONE.

Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade.


 Background. We hypothesized that circulating tumor DNA (ctDNA) can be used as a prognostic biomarker, improve the assessment of response and enhance detection of minimal residual disease in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant therapy (NAT).
 Methods. We analyzed data from 31 LARC patients treated at Memorial Sloan Kettering as part of the Organ Preservation in Rectal Adenocarcinoma (OPRA) phase II clinical trial. Patients had stage II or III rectal adenocarcinoma and received NAT including chemoradiation and chemotherapy. Patients without a clinical complete response (cCR) underwent surgical resection, while patients with a cCR were enrolled in a watch-and-wait protocol for organ preservation. Complete response (CR) after NAT was defined as either pathological complete response or a cCR sustained for ≥2 years. Disease-free survival (DFS) was measured from the start of NAT. Median follow-up was 5.41 years [range 2.96-8.38]. ctDNA analyses were performed using the C2i Genomics platform. A patient-specific molecular profile was created by performing whole-genome sequencing (WGS) of their tumor and matched normal DNA (40x coverage). WGS (20x coverage) was performed on plasma samples collected at baseline (before NAT), interval evaluation (halfway through NAT), re-staging evaluation (8 weeks after NAT) and follow-up (3-6 months after NAT).
 Results. Tumor was detected in plasma samples from 24/25 patients at baseline (96% sensitivity). The tumor fraction (TF) levels detected at baseline separated responders from non-responders (median TF 6.2e-4 vs 1.4e-3; p=0.055). Tumor detection at interval was associated with a lower rate of CR (25% vs. 75%, p=0.0095) and shorter time to recurrence (58.3% vs. 94.1% 3-year DFS, p=0.02). Tumor detection at follow-up was associated with a higher rate of recurrence (p=0.037) and tumor was detected at follow-up for all 5/5 patients who developed recurrence. Overall TF dynamics showed clearance of ctDNA down to the non-detection level throughout treatment in patients with a CR, while non-responders exhibited non-decreasing and often increasing estimates of ctDNA burden. Analysis of tissue WGS data identified multiple patients with colibactin associated mutational signatures, which provides additional insights into their cancer etiology.
 Conclusions. The WGS-based approach for ctDNA analysis exhibited very high sensitivity for detection at baseline. TF across multiple time points separated responders from non-responders, suggesting potential value as a prognostic marker. Detection of ctDNA at follow-up for all patients who recurred is indicative of potential clinical utility for treatment de-escalation in the context of organ preservation strategies.
 Citation Format: Francisco Sanchez-Vega, Chin-Tung Chen, Danielle Afterman, Dana Omer, Madison Darmofal, Ino de Bruijn, Walid K. Chatila, Matthew Drescher, Grittney Tam, Tomer Lauterman, Maja Kuzman, Santiago Gonzalez, Dunja Glavas, James Samdbeck, Dillon Maloney, Jurica Levatic, Sunil Deochand, Michael Yahalom, Ryan Ptashkin, Iman Tavassoly, Zohar Donenhirsh, Eric White, Ravi Kandasamy, Ury Alon, Michael F. Berger, Brian Loomis, Paz Polak, Boris Oklander, Asaf Zviran, Julio Garcia-Aguilar. Ultra-sensitive detection of circulating tumor DNA by whole-genome sequencing of blood samples from locally advanced rectal cancer patients receiving neoadjuvant therapy and enrolled in watch-and-wait strategies for organ preservation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2305.

Abstract 2305: Ultra-sensitive detection of circulating tumor DNA by whole-genome sequencing of blood samples from locally advanced rectal cancer patients receiving neoadjuvant therapy and enrolled in watch-and-wait strategies for organ preservation

Brian R. Loomis

Papers

Surface-Mediated Reactions. 8. Oxidation of Sulfides and Sulfoxides with tert-Butyl Hydroperoxide and OXONE1

Surface-Mediated Reactions. Part 8. Oxidation of Sulfides and Sulfoxides with tert-Butyl Hydroperoxide and OXONE.

Lineage tracing reveals clonal progenitors and long-term persistence of tumor-specific T cells during immune checkpoint blockade.

Abstract 2305: Ultra-sensitive detection of circulating tumor DNA by whole-genome sequencing of blood samples from locally advanced rectal cancer patients receiving neoadjuvant therapy and enrolled in watch-and-wait strategies for organ preservation