Dolastatin 11 conformations, analogues and pharmacophore

Md Ahad Ali; Robert B. Bates; Zackary D. Crane; Christopher W. Dicus; Michelle R. Gramme; Ernest Hamel; Jacob Marcischak; David S. Martinez; Kelly J. McClure; Pichaya Nakkiew; George Pettit; Chad C. Stessman; Bilal A. Sufi; Gayle V. Yarick

doi:10.1016/j.bmc.2005.04.040

Dolastatin 11 conformations, analogues and pharmacophore

Md Ahad Ali, Robert B. Bates, Zackary D. Crane, Christopher W. Dicus, Michelle R. Gramme, Ernest Hamel, Jacob Marcischak, David S. Martinez, Kelly J. McClure, Pichaya Nakkiew, George Pettit, Chad C. Stessman, Bilal A. Sufi, Gayle V. Yarick

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

Twenty analogues of the natural antitumor agent dolastatin 11, including majusculamide C, were synthesized and tested for cytotoxicity against human cancer cells and stimulation of actin polymerization. Only analogues containing the 30-membered ring were active. Molecular modeling and NMR evidence showed the low-energy conformations. The amide bonds are all trans except for the one between the Tyr and Val units, which is cis. Since an analogue restricted to negative 2-3-4-5 angles stimulated actin polymerization but was inactive in cells, the binding conformation (most likely the lowest-energy conformation in water) has a negative 2-3-4-5 angle, whereas a conformation with a positive 2-3-4-5 angle (most likely the lowest energy conformation in chloroform) goes through cell walls. The highly active R alcohol from borohydride reduction of dolastatin 11 is a candidate for conversion to prodrugs.

Original language	English (US)
Pages (from-to)	4138-4152
Number of pages	15
Journal	Bioorganic and Medicinal Chemistry
Volume	13
Issue number	13
DOIs	https://doi.org/10.1016/j.bmc.2005.04.040
State	Published - Jul 1 2005

Keywords

Anticancer
Depsipeptide
Dolastatin 11
Pharmacophore

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmc.2005.04.040

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title = "Dolastatin 11 conformations, analogues and pharmacophore",

abstract = "Twenty analogues of the natural antitumor agent dolastatin 11, including majusculamide C, were synthesized and tested for cytotoxicity against human cancer cells and stimulation of actin polymerization. Only analogues containing the 30-membered ring were active. Molecular modeling and NMR evidence showed the low-energy conformations. The amide bonds are all trans except for the one between the Tyr and Val units, which is cis. Since an analogue restricted to negative 2-3-4-5 angles stimulated actin polymerization but was inactive in cells, the binding conformation (most likely the lowest-energy conformation in water) has a negative 2-3-4-5 angle, whereas a conformation with a positive 2-3-4-5 angle (most likely the lowest energy conformation in chloroform) goes through cell walls. The highly active R alcohol from borohydride reduction of dolastatin 11 is a candidate for conversion to prodrugs.",

keywords = "Anticancer, Depsipeptide, Dolastatin 11, Pharmacophore",

author = "Ali, {Md Ahad} and Bates, {Robert B.} and Crane, {Zackary D.} and Dicus, {Christopher W.} and Gramme, {Michelle R.} and Ernest Hamel and Jacob Marcischak and Martinez, {David S.} and McClure, {Kelly J.} and Pichaya Nakkiew and George Pettit and Stessman, {Chad C.} and Sufi, {Bilal A.} and Yarick, {Gayle V.}",

note = "Funding Information: For financial support, we thank the NIH (grant R01 CA78750), the Camille and Henry Dreyfus Foundation (Senior Scientist Mentor Initiative), the Research Corporation, the Bristol-Myers Squibb Company, and the Aldrich Chemical Company. We are also very grateful to the NCI Developmental Therapeutics Program for testing two compounds against 60 human tumors and to Prof. Richard E. Moore for a generous gift of majusculamide C. ",

year = "2005",

month = jul,

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doi = "10.1016/j.bmc.2005.04.040",

language = "English (US)",

volume = "13",

pages = "4138--4152",

journal = "Bioorganic and Medicinal Chemistry",

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TY - JOUR

T1 - Dolastatin 11 conformations, analogues and pharmacophore

AU - Ali, Md Ahad

AU - Bates, Robert B.

AU - Crane, Zackary D.

AU - Dicus, Christopher W.

AU - Gramme, Michelle R.

AU - Hamel, Ernest

AU - Marcischak, Jacob

AU - Martinez, David S.

AU - McClure, Kelly J.

AU - Nakkiew, Pichaya

AU - Pettit, George

AU - Stessman, Chad C.

AU - Sufi, Bilal A.

AU - Yarick, Gayle V.

N1 - Funding Information: For financial support, we thank the NIH (grant R01 CA78750), the Camille and Henry Dreyfus Foundation (Senior Scientist Mentor Initiative), the Research Corporation, the Bristol-Myers Squibb Company, and the Aldrich Chemical Company. We are also very grateful to the NCI Developmental Therapeutics Program for testing two compounds against 60 human tumors and to Prof. Richard E. Moore for a generous gift of majusculamide C.

PY - 2005/7/1

Y1 - 2005/7/1

N2 - Twenty analogues of the natural antitumor agent dolastatin 11, including majusculamide C, were synthesized and tested for cytotoxicity against human cancer cells and stimulation of actin polymerization. Only analogues containing the 30-membered ring were active. Molecular modeling and NMR evidence showed the low-energy conformations. The amide bonds are all trans except for the one between the Tyr and Val units, which is cis. Since an analogue restricted to negative 2-3-4-5 angles stimulated actin polymerization but was inactive in cells, the binding conformation (most likely the lowest-energy conformation in water) has a negative 2-3-4-5 angle, whereas a conformation with a positive 2-3-4-5 angle (most likely the lowest energy conformation in chloroform) goes through cell walls. The highly active R alcohol from borohydride reduction of dolastatin 11 is a candidate for conversion to prodrugs.

AB - Twenty analogues of the natural antitumor agent dolastatin 11, including majusculamide C, were synthesized and tested for cytotoxicity against human cancer cells and stimulation of actin polymerization. Only analogues containing the 30-membered ring were active. Molecular modeling and NMR evidence showed the low-energy conformations. The amide bonds are all trans except for the one between the Tyr and Val units, which is cis. Since an analogue restricted to negative 2-3-4-5 angles stimulated actin polymerization but was inactive in cells, the binding conformation (most likely the lowest-energy conformation in water) has a negative 2-3-4-5 angle, whereas a conformation with a positive 2-3-4-5 angle (most likely the lowest energy conformation in chloroform) goes through cell walls. The highly active R alcohol from borohydride reduction of dolastatin 11 is a candidate for conversion to prodrugs.

KW - Anticancer

KW - Depsipeptide

KW - Dolastatin 11

KW - Pharmacophore

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Dolastatin 11 conformations, analogues and pharmacophore

Abstract

Keywords

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