The design, computer modeling, solution structure, and biological evaluation of synthetic analogs of bryostatin 1

Paul A. Wender, Jef Debrabander, Patrick G. Harran, Juan Miguel Jimenez, Michael F T Koehler, Blaise Lippa, Cheol Min Park, Carsten Siedenbiedel, George R. Pettit

Research output: Contribution to journalArticle

106 Citations (Scopus)

Abstract

The bryostatins are a unique family of emerging cancer chemotherapeutic candidates isolated from marine bryozoa. Although the biochemical basis for their therapeutic activity is not known, these macrolactones exhibit high affinities for protein kinase C (PKC) isozymes, compete for the phorbol ester binding site on PKC, and stimulate kinase activity in vitro and in vivo. Unlike the phorbol esters, they are not first-stage tumor promoters. The design, computer modeling, NMR solution structure, PKC binding, and functional assays of a unique class of synthetic bryostatin analogs are described. These analogs (7b, 7c, and 8) retain the putative recognition domain of the bryostatins but are simplified through deletions and modifications in the C4-C14 spacer domain. Computer modeling of an analog prototype (7a) indicates that it exists preferentially in two distinct conformational classes, one in close agreement with the crystal structure of bryostatin 1. The solution structure of synthetic analog 7c was determined by NMR spectroscopy and found to be very similar to the previously reported structures of bryostatins 1 and 10. Analogs 7b, 7c, and 8 bound strongly to PKC isozymes with K(i) = 297, 3.4, and 8.3 nM, respectively. Control 7d, like the corresponding bryostatin derivative, exhibited weak PKC affinity, as did the derivative, 9, lacking the spacer domain. Like bryostatin, acetal 7c exhibited significant levels of in vitro growth inhibitory activity (1.8-170 ng/ml) against several human cancer cell lines, providing an important step toward the development of simplified, synthetically accessible analogs of the bryostatins.

Original languageEnglish (US)
Pages (from-to)6624-6629
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number12
DOIs
StatePublished - Jun 9 1998

Fingerprint

Bryostatins
Protein Kinase C
Phorbol Esters
Isoenzymes
Bryozoa
Analogue Computers
Acetals
Carcinogens
bryostatin 1
Neoplasms
Magnetic Resonance Spectroscopy
Binding Sites
Cell Line
Growth

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

The design, computer modeling, solution structure, and biological evaluation of synthetic analogs of bryostatin 1. / Wender, Paul A.; Debrabander, Jef; Harran, Patrick G.; Jimenez, Juan Miguel; Koehler, Michael F T; Lippa, Blaise; Park, Cheol Min; Siedenbiedel, Carsten; Pettit, George R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 95, No. 12, 09.06.1998, p. 6624-6629.

Research output: Contribution to journalArticle

Wender, Paul A. ; Debrabander, Jef ; Harran, Patrick G. ; Jimenez, Juan Miguel ; Koehler, Michael F T ; Lippa, Blaise ; Park, Cheol Min ; Siedenbiedel, Carsten ; Pettit, George R. / The design, computer modeling, solution structure, and biological evaluation of synthetic analogs of bryostatin 1. In: Proceedings of the National Academy of Sciences of the United States of America. 1998 ; Vol. 95, No. 12. pp. 6624-6629.
@article{3a84c4bf75504c6197f92cfda2f0534e,
title = "The design, computer modeling, solution structure, and biological evaluation of synthetic analogs of bryostatin 1",
abstract = "The bryostatins are a unique family of emerging cancer chemotherapeutic candidates isolated from marine bryozoa. Although the biochemical basis for their therapeutic activity is not known, these macrolactones exhibit high affinities for protein kinase C (PKC) isozymes, compete for the phorbol ester binding site on PKC, and stimulate kinase activity in vitro and in vivo. Unlike the phorbol esters, they are not first-stage tumor promoters. The design, computer modeling, NMR solution structure, PKC binding, and functional assays of a unique class of synthetic bryostatin analogs are described. These analogs (7b, 7c, and 8) retain the putative recognition domain of the bryostatins but are simplified through deletions and modifications in the C4-C14 spacer domain. Computer modeling of an analog prototype (7a) indicates that it exists preferentially in two distinct conformational classes, one in close agreement with the crystal structure of bryostatin 1. The solution structure of synthetic analog 7c was determined by NMR spectroscopy and found to be very similar to the previously reported structures of bryostatins 1 and 10. Analogs 7b, 7c, and 8 bound strongly to PKC isozymes with K(i) = 297, 3.4, and 8.3 nM, respectively. Control 7d, like the corresponding bryostatin derivative, exhibited weak PKC affinity, as did the derivative, 9, lacking the spacer domain. Like bryostatin, acetal 7c exhibited significant levels of in vitro growth inhibitory activity (1.8-170 ng/ml) against several human cancer cell lines, providing an important step toward the development of simplified, synthetically accessible analogs of the bryostatins.",
author = "Wender, {Paul A.} and Jef Debrabander and Harran, {Patrick G.} and Jimenez, {Juan Miguel} and Koehler, {Michael F T} and Blaise Lippa and Park, {Cheol Min} and Carsten Siedenbiedel and Pettit, {George R.}",
year = "1998",
month = "6",
day = "9",
doi = "10.1073/pnas.95.12.6624",
language = "English (US)",
volume = "95",
pages = "6624--6629",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "12",

}

TY - JOUR

T1 - The design, computer modeling, solution structure, and biological evaluation of synthetic analogs of bryostatin 1

AU - Wender, Paul A.

AU - Debrabander, Jef

AU - Harran, Patrick G.

AU - Jimenez, Juan Miguel

AU - Koehler, Michael F T

AU - Lippa, Blaise

AU - Park, Cheol Min

AU - Siedenbiedel, Carsten

AU - Pettit, George R.

PY - 1998/6/9

Y1 - 1998/6/9

N2 - The bryostatins are a unique family of emerging cancer chemotherapeutic candidates isolated from marine bryozoa. Although the biochemical basis for their therapeutic activity is not known, these macrolactones exhibit high affinities for protein kinase C (PKC) isozymes, compete for the phorbol ester binding site on PKC, and stimulate kinase activity in vitro and in vivo. Unlike the phorbol esters, they are not first-stage tumor promoters. The design, computer modeling, NMR solution structure, PKC binding, and functional assays of a unique class of synthetic bryostatin analogs are described. These analogs (7b, 7c, and 8) retain the putative recognition domain of the bryostatins but are simplified through deletions and modifications in the C4-C14 spacer domain. Computer modeling of an analog prototype (7a) indicates that it exists preferentially in two distinct conformational classes, one in close agreement with the crystal structure of bryostatin 1. The solution structure of synthetic analog 7c was determined by NMR spectroscopy and found to be very similar to the previously reported structures of bryostatins 1 and 10. Analogs 7b, 7c, and 8 bound strongly to PKC isozymes with K(i) = 297, 3.4, and 8.3 nM, respectively. Control 7d, like the corresponding bryostatin derivative, exhibited weak PKC affinity, as did the derivative, 9, lacking the spacer domain. Like bryostatin, acetal 7c exhibited significant levels of in vitro growth inhibitory activity (1.8-170 ng/ml) against several human cancer cell lines, providing an important step toward the development of simplified, synthetically accessible analogs of the bryostatins.

AB - The bryostatins are a unique family of emerging cancer chemotherapeutic candidates isolated from marine bryozoa. Although the biochemical basis for their therapeutic activity is not known, these macrolactones exhibit high affinities for protein kinase C (PKC) isozymes, compete for the phorbol ester binding site on PKC, and stimulate kinase activity in vitro and in vivo. Unlike the phorbol esters, they are not first-stage tumor promoters. The design, computer modeling, NMR solution structure, PKC binding, and functional assays of a unique class of synthetic bryostatin analogs are described. These analogs (7b, 7c, and 8) retain the putative recognition domain of the bryostatins but are simplified through deletions and modifications in the C4-C14 spacer domain. Computer modeling of an analog prototype (7a) indicates that it exists preferentially in two distinct conformational classes, one in close agreement with the crystal structure of bryostatin 1. The solution structure of synthetic analog 7c was determined by NMR spectroscopy and found to be very similar to the previously reported structures of bryostatins 1 and 10. Analogs 7b, 7c, and 8 bound strongly to PKC isozymes with K(i) = 297, 3.4, and 8.3 nM, respectively. Control 7d, like the corresponding bryostatin derivative, exhibited weak PKC affinity, as did the derivative, 9, lacking the spacer domain. Like bryostatin, acetal 7c exhibited significant levels of in vitro growth inhibitory activity (1.8-170 ng/ml) against several human cancer cell lines, providing an important step toward the development of simplified, synthetically accessible analogs of the bryostatins.

UR - http://www.scopus.com/inward/record.url?scp=0032499759&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032499759&partnerID=8YFLogxK

U2 - 10.1073/pnas.95.12.6624

DO - 10.1073/pnas.95.12.6624

M3 - Article

C2 - 9618462

AN - SCOPUS:0032499759

VL - 95

SP - 6624

EP - 6629

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 12

ER -