Structure-activity relationship study of hypoxia-activated prodrugs for proteoglycan-targeted chemotherapy in chondrosarcoma was written by Ghedira, Donia;Voissiere, Aurelien;Peyrode, Caroline;Kraiem, Jamil;Gerard, Yvain;Maubert, Elise;Vivier, Magali;Miot-Noirault, Elisabeth;Chezal, Jean-Michel;Farhat, Farhat;Weber, Valerie. And the article was included in European Journal of Medicinal Chemistry in 2018.SDS of cas: 954-81-4 This article mentions the following:
Due to an abundant chondrogenic, poorly vascularized and particularly hypoxic extracellular matrix, chondrosarcoma, a malignant cartilaginous tumor, is chemo- and radio-resistant. Surgical resection with wide margins remains the mainstay of treatment. To address the lack of therapy, our strategy aims to increase anticancer drugs targeting and delivery in the tumor, by leveraging specific chondrosarcoma hallmarks: an extensive cartilaginous extracellular matrix, namely the high neg. fixed charge d. and severe chronic hypoxia. A dual targeted therapy for chondrosarcoma was investigated by conjugation of a hypoxia-activated prodrug (HAP) to quaternary ammonium (QA) functions which exhibit a high affinity for polyanionic sites of proteoglycans (PGs), the major components of the chondrosarcoma extracellular matrix. Based on preclin. results, an imidazole prodrug, ICF05016, was identified and provided the basis for a lead optimization study. A series of 27 QA-phosphoramide mustard conjugates, differing by the type of QA function and the length of the alkyl linker, was yielded by a common multi-step sequence involving phosphorylation of a key 2-nitroimidazole alc. Then, a screening was realized by surface plasmon resonance technol. to assess biomol. interactions between QA derivatives and aggrecan, the most abundant PG in chondrosarcoma. Results revealed that affinity depends more on the type of QA function, than on the linker length. Moreover, the presence of a benzyl group enhanced affinity to aggrecan. Twelve compounds were shortlisted and evaluated for antiproliferative activity (i.e., growth inhibiting concentration 50), under normoxic and hypoxic conditions using the human extraskeletal myeloid chondrosarcoma cell line (HEMC-SS). For all prodrugs, hypoxic selectivity was maintained and even increased, compared with the lead. From this study, compound I emerged as the most effective PG-targeted HAPs with a dissociation constant of 2.10 娓璏 in the SPR experiment, a hypoxia cytotoxicity ratio of 24 and an efficient reductive cleavage under chem. and enzymic conditions. In the experiment, the researchers used many compounds, for example, N-(5-Bromopentyl)phthalimide (cas: 954-81-4SDS of cas: 954-81-4).
N-(5-Bromopentyl)phthalimide (cas: 954-81-4) belongs to organobromine compounds. Many of the organo bromine compounds are relatively nonpolar. Bromine is more electronegative than carbon (2.8 vs 2.5) and hence the carbon in a carbon鑱砨romine bond is electrophilic in nature. Commercially available organobromine pharmaceuticals include the vasodilator nicergoline, the sedative brotizolam, the anticancer agent pipobroman, and the antiseptic merbromin. SDS of cas: 954-81-4
Referemce:
Bromide – Wikipedia,
bromide – Wiktionary