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. 2017 Jun 15;25(12):3206-3214.
doi: 10.1016/j.bmc.2017.04.012. Epub 2017 Apr 11.

Ortho group activation of a bromopyrrole ester in Suzuki-Miyaura cross-coupling reactions: Application to the synthesis of new microtubule depolymerizing agents with potent cytotoxic activities

John T Gupton  1 , Scott Yeudall  2 , Nakul Telang  2 , Megan Hoerrner  2 , Ellis Huff  2 , Evan Crawford  2 , Katie Lounsbury  2 , Michael Kimmel  2 , William Curry  2 , Andrew Harrison  2 , Wen Juekun  2 , Alex Shimozono  2 , Joe Ortolani  2 , Kristin Lescalleet  2 , Jon Patteson  2 , Veronica Moore-Stoll  2 , Cristina C Rohena  3 , Susan L Mooberry  3 , Ahmad J Obaidullah  4 , Glen E Kellogg  4 , James A Sikorski  5
Affiliations

Ortho group activation of a bromopyrrole ester in Suzuki-Miyaura cross-coupling reactions: Application to the synthesis of new microtubule depolymerizing agents with potent cytotoxic activities

John T Gupton et al. Bioorg Med Chem. .

Abstract

New microtubule depolymerizing agents with potent cytotoxic activities have been prepared with a 5-cyano or 5-oximino group attached to a pyrrole core. The utilization of ortho activation of a bromopyrrole ester to facilitate successful Suzuki-Miyaura cross-coupling reactions was a key aspect of the synthetic methodology. This strategy allows for control of regiochemistry with the attachment of four completely different groups at the 2, 3, 4 and 5 positions of the pyrrole scaffold. Biological evaluations and molecular modeling studies are reported for these examples.

Keywords: Cytotoxic activity; Marine natural products; Microtubule inhibitors; Pyrrole; Suzuki-Miyaura cross-coupling.

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Figures

Fig. 1
Fig. 1
Examples of two bioactive, synthetic pyrroles
Figure 2
Figure 2
Effects of NT-7-45 isomeric mixture on cellular microtubules
Figure 3
Figure 3
NT-7-45 inhibits tumor growth in a MDA-MB-435 xenograft model *** p = 0.0005, ***** p < 0.0001, * p = 0.04.
Fig. 4
Fig. 4
Computational model of NT-7-16, KL-3-95, NT-7-45 (Z) and NT-7-45 (E) in the colchicine Binding site of β-tubulin. Inset: close-up of substitutions at the 5-position of pyrrole. Note: beige – NT-7-16; cyan – KL-3-95; orange – NT-7-45 (E); magenta – NT-7-45 (Z)
Scheme 1
Scheme 1
Suzuki-Miyaura Cross-Coupling studies of 4-bromo-2-carbethoxypyrrole
Scheme 2
Scheme 2
Preparation of 4-bromo-5-cyano-2-carbethoxypyrrole building block
Scheme 3
Scheme 3
Suzuki-Miyaura cross-coupling reactions of ethyl 3-bromo-2-cyanopyrrole-5-carboxylate with various aryl and heteroarylboronic acid derivatives
Scheme 4
Scheme 4
Preparation of 5-cyano position analog of NT-7-16
Scheme 5
Scheme 5
Preparation of the 5-position oxime analog of NT-7-16
See this image and copyright information in PMC

References

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