Factors affecting receipt of chemotherapy in women with breast cancer

Libby Morimoto1, Jenna Coalson1, Fionna Mowat1, Cynthia O’Malley21Exponent Health Sciences, Menlo Park, CA, USA; 2Amgen Global Epidemiology, Thousand Oaks, CA, USAAims: To review literature describing factors associated with receipt of chemotherapy for breast cancer, to better understand what factors are most relevant to women’s health and whether health disparities are apparent, and to assess how these factors might affect observational studies and outcomes research. Patterns of care for metastatic breast cancer, for which no standard-of-care exists, were of particular interest.Methods: Relevant studies written in English, Italian, French, or Spanish, published in 2000 or later, were identified through MEDLINE and reviewed. Review articles and clinical trials were excluded; all observational studies and surveys were considered. Articles were reviewed for any discussion of patient characteristics, hospital/physician/insurance characteristics, psychosocial characteristics, and clinical characteristics affecting receipt of chemotherapy by breast cancer patients.Results: In general, factors associated with increased likelihood of receiving chemotherapy included younger age, being Caucasian, having good general health and few co-morbidities, having more severe clinical disease, having responded well to previous treatment, and having breast cancer that is estrogen- or progesterone-receptor-negative. Many of the clinical factors found to increase the likelihood of receiving chemotherapy were consistent with current oncology guidelines. Of the relevant 19 studies identified, only six (32%) reported data specific to metastatic cancer; most studies aggregated women with stage I–IV for purposes of analysis.Conclusion: Studies of patterns of care in breast cancer treatment can help identify challenges in health care provided to particular subgroups of women and can aid researchers in designing studies that account for such factors in clinical and outcomes research. Although scarce, studies evaluating only women with metastatic breast cancer indicate that factors affecting decisions related to receipt of chemotherapy are similar across stage for this disease.Keywords: breast cancer, chemotherapy, metastatic, treatment decisions, health disparitie

Synthesis of 2-BMIDA 6,5-bicyclic heterocycles by Cu(I)/Pd(0)/Cu(II) cascade catalysis of 2-iodoaniline/phenols

A one-pot cascade reaction for the synthesis of 2-BMIDA 6,5-bicyclic heterocycles has been developed using Cu(I)/Pd(0)/Cu(II) catalysis. 2-Iodoanilines and phenols undergo a Cu(I)/Pd(0)-catalyzed Sonogashira reaction with ethynyl BMIDA followed by in situ Cu(II)-catalyzed 5-endo-dig cyclization to generate heterocyclic scaffolds with a BMIDA functional group in the 2-position. The method provides efficient access to borylated indoles, benzofurans, and aza-derivatives, which can be difficult to access through alternative methods

Metal free C-C bond formation via coupling of nitrile imines and boronic acids

The challenges of developing sustainable methods of carbon-carbon bond formation remains a topic of considerable importance in synthetic chemistry. Capitalizing on the highly reactive nature of the nitrile imine 1,3-dipole, we have developed a novel metal-free coupling of this species with aryl boronic acids. Photochemical generation of a nitrile imine intermediate and trapping with a palette of boronic acids enabled rapid and facile access to a broad library of more than 25 hydrazone derivatives in up to 92 % yield, forming a carbon-carbon bond in a metal free fashion. This represents the first reported example of direct reaction between boronic acids and a 1,3-dipole

Functionalized tetrazoles as latent active esters in the synthesis of amide bonds

We report the use of N-2,4-dinitrophenyltetrazoles as latent active esters (LAEs) in the synthesis of amide bonds. Activating the tetrazole generates an HOBt-type active ester without the requirement for exogenous coupling agents. The methodology was widely applicable to a range of substrates, with up to quantitative yields obtained. The versatility and functional group tolerance were exemplified with the one-step synthesis of various pharmaceutical agents, and the N-acylation of resin bound peptides

Development of new synthetic approaches in solid-phase peptide synthesis

Chapter 1 of this thesis will focus on the development of a synthetic route to access dual-labelled peptides using bioorthogonal reacting pairs. Since its inception in 2003, bioorthogonal chemistry is a growing area of chemistry which has greatly aided in the studies of biomolecules. We have developed a route which could facilitate the selective and sequential labelling of biomolecules through means of leveraging chemistry highlighted in literature. We have employed two orthogonal reacting pairs, nitrile imines with carboxylic acids and azides with aromatic ynamines, Figure 1. [Figure reproduced in thesis text] Nitrile imines are highly reactive 1,3-dipoles which can be accessed in situ through the photolytic degradation of 2,5-diaryl tetrazoles. Given their inherent dipole, they can undergo 1,3-dipolar cycloadditions as expected, however, through competition experimental studies we have shown that NIs will preferentially react with carboxylic acids when exposed to a dipolarophile, such as an aromatic ynamine. Aromatic ynamines have been shown to provide high selectivity in CuAAC over aliphatic alkynes. We have shown that both of these processes can occur orthogonally to one another and can be applied to a biomolecule setting, Scheme 1. [Figure reproduced in thesis text] Chapter 2 of this report will shift the focus onto the solvents used to synthesise peptides. Typically, the solvent of choice employed in SPPS is N,N’-dimethylformamide (DMF) which is highly toxic as it is teratogenic and with that, restrictions around its sale and manufacture are being tightened as of December 2023. Therefore, the requirement to identify a robust replacement for this crucial process is of the utmost importance. We report the development of an interactive solvent selection guide for SPPS and conduct studies examining solvents ability to swell resins in addition to solubilising amino acids and coupling reagents which identified cyclopentanone as a potential candidate to replace DMF, and when applied to SPPS, we were successful in synthesising a pentapeptide with good crude purity.Chapter 1 of this thesis will focus on the development of a synthetic route to access dual-labelled peptides using bioorthogonal reacting pairs. Since its inception in 2003, bioorthogonal chemistry is a growing area of chemistry which has greatly aided in the studies of biomolecules. We have developed a route which could facilitate the selective and sequential labelling of biomolecules through means of leveraging chemistry highlighted in literature. We have employed two orthogonal reacting pairs, nitrile imines with carboxylic acids and azides with aromatic ynamines, Figure 1. [Figure reproduced in thesis text] Nitrile imines are highly reactive 1,3-dipoles which can be accessed in situ through the photolytic degradation of 2,5-diaryl tetrazoles. Given their inherent dipole, they can undergo 1,3-dipolar cycloadditions as expected, however, through competition experimental studies we have shown that NIs will preferentially react with carboxylic acids when exposed to a dipolarophile, such as an aromatic ynamine. Aromatic ynamines have been shown to provide high selectivity in CuAAC over aliphatic alkynes. We have shown that both of these processes can occur orthogonally to one another and can be applied to a biomolecule setting, Scheme 1. [Figure reproduced in thesis text] Chapter 2 of this report will shift the focus onto the solvents used to synthesise peptides. Typically, the solvent of choice employed in SPPS is N,N’-dimethylformamide (DMF) which is highly toxic as it is teratogenic and with that, restrictions around its sale and manufacture are being tightened as of December 2023. Therefore, the requirement to identify a robust replacement for this crucial process is of the utmost importance. We report the development of an interactive solvent selection guide for SPPS and conduct studies examining solvents ability to swell resins in addition to solubilising amino acids and coupling reagents which identified cyclopentanone as a potential candidate to replace DMF, and when applied to SPPS, we were successful in synthesising a pentapeptide with good crude purity

Synthesis of 2-BMIDA 6,5-bicyclic heterocycles by Cu(I)/Pd(0)/Cu(II) cascade catalysis of 2-iodoaniline/phenols

A one-pot cascade reaction for the synthesis of 2-BMIDA 6,5-bicyclic heterocycles has been developed using Cu(I)/Pd(0)/Cu(II) catalysis. 2-Iodoanilines and phenols undergo a Cu(I)/Pd(0)-catalyzed Sonogashira reaction with ethynyl BMIDA followed by in situ Cu(II)-catalyzed 5-endo-dig cyclization to generate heterocyclic scaffolds with a BMIDA functional group in the 2-position. The method provides efficient access to borylated indoles, benzofurans, and aza-derivatives, which can be difficult to access through alternative methods

A fragment-like approach to PYCR1 inhibition

Pyrroline-5-carboxylate reductase 1 (PYCR1) is the final enzyme involved in the biosynthesis of proline and has been found to be upregulated in various forms of cancer. Due to the role of proline in maintaining the redox balance of cells and preventing apoptosis, PYCR1 is emerging as an attractive oncology target. Previous PYCR1 knockout studies led to a reduction in tumor growth. Accordingly, a small molecule inhibitor of PYCR1 could lead to new treatments for cancer, and a focused screening effort identified pargyline as a fragment-like hit. We report the design and synthesis of the first tool compounds as PYCR1 inhibitors, derived from pargyline, which were assayed to assess their ability to attenuate the production of proline. Structural activity studies have revealed the key determinants of activity, with the most potent compound (4) showing improved activity in vitro in enzyme (IC50 = 8.8 µM) and pathway relevant effects in cell-based assays

Calgary Wetlands Clean-up and Preservation Proposal

The University of Calgary, Indigenous Studies “Ecological Knowledge” (INDG 317) taught by Professor Line Laplante aims to educate students about ways that the environment communicates using traditional Indigenous ways of knowing. Throughout the course, students learn how to apply traditional Indigenous ecological knowledge, philosophies, and teachings to modern issues. The overarching goal of the curriculum is to provide students with tools to address environment and climate changes that integrate the 2015 Truth and Reconciliation Commission (TRC) Report recommendations, as well as influence urban planning to include a renewed focus on promoting and preserving biodiversity. The 2018 Ecological Knowledge summer class developed this proposal to incorporate experiential knowledge acquired this semester to contribute towards Calgary’s growth as a culturally respectful, biologically ethical, and thriving city. This proposal supports and enhances the Our BiodiverCity (2015) strategic plan and the City of Calgary’s fundamental principles of “protecting, developing, and managing” natural environments