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. 2017 Aug 4;82(15):7720-7731.
doi: 10.1021/acs.joc.7b01162. Epub 2017 Jul 25.

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

Alyssa H Antropow  1 , Kun Xu, Rachel J Buchsbaum, Mohammad Movassaghi  1
Affiliations

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

Alyssa H Antropow et al. J Org Chem. .

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 coculture 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 noncytotoxic 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.

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Conflict of interest statement

Notes

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Structures of (−)-agelastatins A–F (1–6).
Figure 2
Figure 2
Retrosynthetic analysis of agelastatin alkaloid derivatives.
Figure 3
Figure 3
AgE (5) blocks stimulated transcription of osteopontin in fibroblasts. VitD = vitamin D.
Figure 4
Figure 4
Effect of AgA (1) and AgE (5) on breast cancer cell invasion in co-cultures with mammary fibroblasts. Number of projections per spheroid for SUM1315 breast cancer cells and indicated mammary fibroblasts in 3D mixed cell spheroid co-culture is shown as percent of total spheroids. shC = control silencing retroviral hairpin vector. shTiam = Tiam1 silencing hairpin vector.
Figure 5
Figure 5
Effect of AgE (5) on migration potential of breast cancer cells isolated from co-culture with mammary fibroblasts.
Figure 6
Figure 6
Effect of AgA (1) and AgE (5) on tumorsphere formation by breast cancer cells isolated from co-culture with mammary fibroblasts.
Figure 7
Figure 7
Effect of AgA (1) and AgE (5) on CD44+/CD24−/ESA+ populations in breast cancer cells isolated from co-culture with mammary fibroblasts.
Figure 8
Figure 8
Varying effects of agelastatin derivatives in blocking stimulated fibroblast expression of osteopontin. All agelastatin derivatives were tested at 100-nM concentration unless noted otherwise. * indicates statistical equivalence with AgA (1) at 100-nM concentration; ** indicates equivalence with AgE (5) at 50-nM concentration, but not AgA (1) at 100-nM concentration by T-test. No Tx = baseline control with values normalized to transcription of a housekeeping gene.
Scheme 1
Scheme 1
Chemical diversification of AgE derivatives 7e–7h. Conditions: (a) PPh3, THF–H2O (9:1). (b) 4-nitrophenyl 2-(trimethylsilyl)ethyl carbonate, NEt3, CH2Cl2. (c) Ac2O, NEt3, DMAP, THF. (d) BzCl, NEt3, THF.
Scheme 2
Scheme 2
Observed double cyclization of tricycle 11a to pentacycle 14. Conditions: (a) MeSO3H, H2O, 100 °C.
Scheme 3
Scheme 3
Chemical diversification of AgA derivatives 8b and 8c to the corresponding azides. Conditions: PPh3 (n equiv), diisopropylazodicarboxylate (n equiv), diphenyl phosphoryl azide (n equiv), THF. (a) n = 2, 8d isolated along with 34% recovered starting material. (b) n = 10.
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