Synthesis and Evaluation of Agelastatin Derivatives as Potent Modulators for Cancer Invasion and Metastasis

Abstract

The synthesis of new agelastatin alkaloid derivatives and their anticancer evaluation in the context of the breast cancer microenvironment is described. A variety of N1-alkyl and C5-ether agelastatin derivatives were accessed via application of our strategy for convergent imidazolone synthesis from a common thioester along with appropriately substituted urea and alcohol components. These agelastatin derivatives were evaluated in our three-dimensional co-culture assay for the effects of mammary fibroblasts on associated breast cancer cells. We have discovered that agelastatin alkaloids are potent modulators for cancer invasion and metastasis at non-cytotoxic doses. Herein we discuss the increased potency of (−)-agelastatin E as compared to (−)-agelastatin A in this capacity, in addition to identification of new agelastatin derivatives with activity that is statistically equivalent to (−)-agelastatin E. The chemistry described in this report provides a platform for the rapid synthesis of agelastatin derivatives with excellent potency (50–100 nM) as modulators for cancer invasion and metastasis.

Unusually Reactive Cyclic Anhydride Expands the Scope of the Castagnoli–Cushman Reaction

“…It should be noted that the 3,4-dihydro­pyr­rolo­[1,2- a ]­pyrazin-1­(2 H )-one core featured in compounds 8a – u (as well as in their N -aryl counterparts 9a – d ) clearly belongs to privileged heterocyclic scaffolds capable of displaying widely variable biological activities depending on the specific molecular periphery employed . Indeed, just by reviewing the biomedical literature over the last 2 years, one can encounter notable examples of mGluR2 receptor antagonist 10 , compound capable of reducing blood uric acid levels 11 , inhibitor of mycobacterial ATP synthase 12 , and ERK1/2 kinase inhibitor 13 ; moreover, this core is central to (−)-agelastatin alkaloids of general formula 14 endowed with promising anticancer activity (Figure ). Thus, besides the remarkably reactive character of 1o in the context of the CCR, the privileged nature of the 3,4-dihydro­pyr­rolo­[1,2- a ]­pyrazin-1­(2 H )-one motif for drug design clearly adds value to the approach discussed herein.…”

Combining photochemical transformation of pyridinium salt with kinetic enzymatic resolution towards the total synthesis of (-)-agelastatin A

“…AglA is more potent and more desired than all its natural and synthetic analogues. 3,6,7 In addition to its high cytotoxicity against a variety of human tumour cell-lines, 3 AglA strongly inhibits osteopontin-mediated neoplastic transformation and metastasis, 8 heavily implicated in cancer progression. Additionally, it displays high brine shrimp toxicity and insecticidal properties.…”

Tumor microenvironment: a prospective target of natural alkaloids for cancer treatment

“…Specifically, OPN transcription and secretion are induced by negative regulation of the Rac GTPase exchange factor Tiam1. Beyond that, down-regulation of fibroblast Tiam1 and up-regulation of fibroblast OPN in the TME increased invasiveness in human breast cancers [ 32 , 33 ].…”