Abstract
Dialkyl phosphinates are valuable peptide mimics fo r metallopeptidase targets. Despite their large pharmaceutical potential, the synthesis of many pho sphinates remains challenging. An additional drawback for many applications is the high polarity of the phosphinate group. Herein we describe the synthesis of stereoisomerically pure GPI ( 1), a phosphinate with high binding affinity for the cancer specific zinc peptidase PSMA (prostate speci fic membrane antigen). In addition, analogous cyclic phosphinate esters 13 , 16 and 23 are reported that might be useful as less polar li gands for metallo peptidase binding. The key step to these ne w 1,2-oxaphosphorinan-2-ones is an intramolecular cyclization of an intermediate H-phosphinate. The cyclizations work with modest diastereoselectivities of ~2:1 in favor of the trans arrangement of substituents at 2- and 4-position of the 1,2-oxaphosphorinan-2-one scaffolds.
Highlights
Zinc containing peptidases constitute an important class of enzymes involved in tumor progression, angiogenesis, embryogenesis, ovulation and differentiation.[1,2] An altered level of expression is often associated with malignant neoplasy
We describe the synthesis of stereoisomerically pure GPI (1), a phosphinate with high binding affinity for the cancer specific zinc peptidase PSMA
The cyclizations work with modest diastereoselectivities of ~2:1 in favor of the trans arrangement of substituents at 2- and 4-position of the 1,2-oxaphosphorinan-2-one scaffolds
Summary
Zinc containing peptidases constitute an important class of enzymes involved in tumor progression, angiogenesis, embryogenesis, ovulation and differentiation.[1,2] An altered level of expression is often associated with malignant neoplasy. The resulting mixture was stirred for 1 h at 0 °C and a solution of 5 (1.00 g, 3.10 mmol, 1.00 eq.) in dry CH2Cl2 (1.1 mL) was added.
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