Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2013 Feb 14;56(3):628-39.
doi: 10.1021/jm3015684. Epub 2012 Dec 17.

A remarkable series of vinblastine analogues displaying enhanced activity and an unprecedented tubulin binding steric tolerance: C20' urea derivatives

Erick K Leggans  1 , Katharine K Duncan, Timothy J Barker, Kristin D Schleicher, Dale L Boger
Affiliations

A remarkable series of vinblastine analogues displaying enhanced activity and an unprecedented tubulin binding steric tolerance: C20' urea derivatives

Erick K Leggans et al. J Med Chem. .

Abstract

A systematic series of previously inaccessible key C20' urea and thiourea derivatives of vinblastine were prepared from 20'-aminovinblastine that was made accessible through a unique Fe(III)/NaBH(4)-mediated alkene functionalization reaction of anhydrovinblastine. Their examination defined key structural features of the urea-based analogues that contribute to their properties and provided derivatives that match or exceed the potency of vinblastine by as much as 10-fold in cell-based functional assays, which is directly related to their relative tubulin binding affinity. In contrast to expectations based on apparent steric constraints of the tubulin binding site surrounding the vinblastine C20' center depicted in an X-ray cocrystal structure, remarkably large C20' urea derivatives are accommodated.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Top: Natural products and initial C20' vinblastine analogues. Bottom: x-ray structure of vinblastine bound to tubulin highlighting the region surrounding vinblastine C20' site (PDB ID: 1Z2B).
Figure 2
Figure 2
Activity of vinblastine C20' urea analogues
Figure 3
Figure 3
Unprecedented C20' steric tolerance
Figure 4
Figure 4
Activity of vinblastine C20' thiourea analogues
Figure 5
Figure 5
Activity of vinblastine C20' disubstituted urea and thiourea analogues
Figure 6
Figure 6
Importance of the C20' amine versus alcohol functionalization and distinctions between urea/thiourea versus carbamate/amide derivatives
Figure 7
Figure 7
Activity of C20' amines
Figure 8
Figure 8
Impact of C20' nitrogen H-bond donor
Figure 9
Figure 9
Urea derivative of 10'-fluorovinblastine
Figure 10
Figure 10
Tubulin binding assay
Scheme 1
Scheme 1
Scheme 2
Scheme 2
See this image and copyright information in PMC

References

    1. (a) Review: Neuss N, Neuss MN. Therapeutic use of bisindole alkaloids from catharanthus. In: Brossi A, Suffness M, editors. The Alkaloids. Vol. 37. San Diego: Academic; 1990. pp. 229–240. (b) Review: Pearce HL. Medicinal chemistry of bisindole alkaloids from catharanthus. In: Brossi A, Suffness M, editors. The Alkaloids. Vol. 37. San Diego: Academic; 1990. pp. 145–204. (c) Review: Kuehne ME, Marko I. Syntheses of vinblastine-type alkaloids. In: Brossi A, Suffness M, editors. The Alkaloids. Vol. 37. San Diego: Academic; 1990. pp. 77–132.

    1. Noble RL, Beer CT, Cutts JH. Role of chance observations in chemotherapy: Vinca rosea. Ann. N. Y. Acad. Sci. 1958;76:882–894. - PubMed
    2. Noble RL. Catharanthus roseus (vinca rosea) - importance and value of a chance observation. Lloydia. 1964;27:280–281.
    3. Svoboda GH, Nuess N, Gorman M. Alkaloids of Vinca rosea Linn. (Catharanthus roseus G. Don.). V. Preparation and characterization of alkaloids. J. Am. Pharm. Assoc. Sci. Ed. 1959;48:659–666. - PubMed
    1. Noble RL. Catharanthus roseus (vinca rosea) - importance and value of a chance observation. Lloydia. 1964;27:280–281.
    2. Svoboda GH, Nuess N, Gorman M. Alkaloids of Vinca rosea Linn. (Catharanthus roseus G. Don.). V. Preparation and characterization of alkaloids. J. Am. Pharm. Assoc. Sci. Ed. 1959;48:659–666. - PubMed
    1. Fahy J. Modifications in the “upper” velbenamine part of the Vinca alkaloids have major implications for tubulin interacting activities. Curr. Pharm. Design. 2001;7:1181–1197. - PubMed
    2. Potier P. Synthesis of the antitumor dimeric indole alkaloids from catharanthus species (vinblastine group) J. Nat. Prod. 1980;43:72–86.
    3. Kutney JP. Plant cell culture combined with chemistry: a powerful route to complex natural products. Acc. Chem. Res. 1993;26:559–566.
    4. Miyazaki T, Yokoshima S, Simizu S, Osada H, Tokuyama H, Fukuyama T. Synthesis of (+)-vinblastine and its analogues. Org. Lett. 2007;9:4737–4740. - PubMed
    1. Langlois N, Gueritte F, Langlois Y, Potier P. Application of a modification of the Polonovski reaction to the synthesis of vinblastine-type alkaloids. J. Am. Chem. Soc. 1976;98:7017–7024. - PubMed
    2. Kuehne ME, Matson PA, Bornmann WG. Enantioselective syntheses of vinblastine, leurosidine, vincovaline and 20’-epi-vincovaline. J. Org. Chem. 1991;56:513–528.
    3. Bornmann WG, Kuehne ME. A common intermediate providing syntheses of Ψ-tabersonine, coronaridine, iboxyphylline, ibophyllidine, vinamidine, and vinblastine. J. Org. Chem. 1992;57:1752–1760.
    4. Yokoshima S, Ueda T, Kobayashi S, Sato A, Kuboyama T, Tokuyama H, Fukuyama T. Stereocontrolled total synthesis of (+)-vinblastine. J. Am. Chem. Soc. 2002;124:2137–2139. - PubMed
    5. Kuboyama T, Yokoshima S, Tokuyama H, Fukuyama T. Stereocontrolled total synthesis of (+)-vincristine. Proc. Natl. Acad. Sci. USA. 2004;101:11966–11970. - PMC - PubMed

Publication types

MeSH terms