Synthesis and biological activities of new conformationally restricted analogues of (-)-indolactam-V: Elucidation of the biologically active conformation of the tumor-promoting teleocidins

Kazuhiro Irie, Tomomi Isaka, Yoriko Iwata, Yoshiaki Yanai, Yoshimasa Nakamura, Fumito Koizumi, Hajime Ohigashi, Paul A. Wender, Yoshiko Satomi, Hoyoku Nishino

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

The tumor-promoting teleocidins and their core structure (-)-indolactam-V (1) exist in two stable conformers in solution at room temperature. The cis amide assumes a twist conformation while the trans amide exists in a sofa form. In order to identify the biologically active conformation of the teleocidins, we have synthesized new twist-restricted analogues 5a and 6 based on an aza-Claisen rearrangement of (-)-N13-desmethyl-N13-allylindolactam-V (3) and a sofa-restricted analogue, (-)-5-methylindolactam-V (22). The activities of these new compounds were evaluated in three in vitro bioassays associated with in vivo tumor-promoting activity: binding to the protein kinase C regulatory domain, induction of the Epstein-Barr virus early antigen, and stimulation of radioactive inorganic phosphate incorporation into phospholipids of HeLa cells. These three biological activities correlated well for each derivative. Twist-restricted analogues 5a and 6 showed significant activities in the three assays, comparable to 1 itself. In contrast, sofa-restricted 22 showed little activity related to tumor promotion. Introduction of a prenyl group into position 7 or 18 of 5a and 6 significantly enhanced the activity while sofa-restricted (-)-5-prenylindolactam-V (23) showed only very weak activity. These results indicate that the active conformation of the teleocidins and 1 is close to the twist form. This is the first evidence bearing on the active conformation of the teleocidins based on conformationally restricted analogues with an intact indolactam skeleton and is in accord with conclusions reported for benzolactams, analogues without the pyrrole moiety. This study also describes the synthesis of new biologically active compounds (26a, 26b, 28) based on inactive (+)-epiindolactam-V (24), involving a further application of the aza-Claisen rearrangement. Bridge formation between positions 5 and 13 of indolactam derivatives represents a particularly effective analogue design strategy, allowing for the remote control of the conformation of this ring system and for the introduction of a wide range of structural variations, as required for the development of new protein kinase C activators with high isozyme selectivity.

Original languageEnglish
Pages (from-to)10733-10743
Number of pages11
JournalJournal of the American Chemical Society
Volume118
Issue number44
DOIs
Publication statusPublished - Nov 6 1996
Externally publishedYes

Fingerprint

Bioactivity
Conformations
Tumors
Amides
Protein Kinase C
Neoplasms
Bearings (structural)
Pyrroles
Derivatives
Proteins
HeLa Cells
Skeleton
Biological Assay
Bioassay
Isoenzymes
Phospholipids
Antigens
Remote control
Carrier Proteins
Viruses

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Synthesis and biological activities of new conformationally restricted analogues of (-)-indolactam-V : Elucidation of the biologically active conformation of the tumor-promoting teleocidins. / Irie, Kazuhiro; Isaka, Tomomi; Iwata, Yoriko; Yanai, Yoshiaki; Nakamura, Yoshimasa; Koizumi, Fumito; Ohigashi, Hajime; Wender, Paul A.; Satomi, Yoshiko; Nishino, Hoyoku.

In: Journal of the American Chemical Society, Vol. 118, No. 44, 06.11.1996, p. 10733-10743.

Research output: Contribution to journalArticle

Irie, Kazuhiro ; Isaka, Tomomi ; Iwata, Yoriko ; Yanai, Yoshiaki ; Nakamura, Yoshimasa ; Koizumi, Fumito ; Ohigashi, Hajime ; Wender, Paul A. ; Satomi, Yoshiko ; Nishino, Hoyoku. / Synthesis and biological activities of new conformationally restricted analogues of (-)-indolactam-V : Elucidation of the biologically active conformation of the tumor-promoting teleocidins. In: Journal of the American Chemical Society. 1996 ; Vol. 118, No. 44. pp. 10733-10743.
@article{97d70362a82a4e78b2a52574e46deca4,
title = "Synthesis and biological activities of new conformationally restricted analogues of (-)-indolactam-V: Elucidation of the biologically active conformation of the tumor-promoting teleocidins",
abstract = "The tumor-promoting teleocidins and their core structure (-)-indolactam-V (1) exist in two stable conformers in solution at room temperature. The cis amide assumes a twist conformation while the trans amide exists in a sofa form. In order to identify the biologically active conformation of the teleocidins, we have synthesized new twist-restricted analogues 5a and 6 based on an aza-Claisen rearrangement of (-)-N13-desmethyl-N13-allylindolactam-V (3) and a sofa-restricted analogue, (-)-5-methylindolactam-V (22). The activities of these new compounds were evaluated in three in vitro bioassays associated with in vivo tumor-promoting activity: binding to the protein kinase C regulatory domain, induction of the Epstein-Barr virus early antigen, and stimulation of radioactive inorganic phosphate incorporation into phospholipids of HeLa cells. These three biological activities correlated well for each derivative. Twist-restricted analogues 5a and 6 showed significant activities in the three assays, comparable to 1 itself. In contrast, sofa-restricted 22 showed little activity related to tumor promotion. Introduction of a prenyl group into position 7 or 18 of 5a and 6 significantly enhanced the activity while sofa-restricted (-)-5-prenylindolactam-V (23) showed only very weak activity. These results indicate that the active conformation of the teleocidins and 1 is close to the twist form. This is the first evidence bearing on the active conformation of the teleocidins based on conformationally restricted analogues with an intact indolactam skeleton and is in accord with conclusions reported for benzolactams, analogues without the pyrrole moiety. This study also describes the synthesis of new biologically active compounds (26a, 26b, 28) based on inactive (+)-epiindolactam-V (24), involving a further application of the aza-Claisen rearrangement. Bridge formation between positions 5 and 13 of indolactam derivatives represents a particularly effective analogue design strategy, allowing for the remote control of the conformation of this ring system and for the introduction of a wide range of structural variations, as required for the development of new protein kinase C activators with high isozyme selectivity.",
author = "Kazuhiro Irie and Tomomi Isaka and Yoriko Iwata and Yoshiaki Yanai and Yoshimasa Nakamura and Fumito Koizumi and Hajime Ohigashi and Wender, {Paul A.} and Yoshiko Satomi and Hoyoku Nishino",
year = "1996",
month = "11",
day = "6",
doi = "10.1021/ja961727j",
language = "English",
volume = "118",
pages = "10733--10743",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "44",

}

TY - JOUR

T1 - Synthesis and biological activities of new conformationally restricted analogues of (-)-indolactam-V

T2 - Elucidation of the biologically active conformation of the tumor-promoting teleocidins

AU - Irie, Kazuhiro

AU - Isaka, Tomomi

AU - Iwata, Yoriko

AU - Yanai, Yoshiaki

AU - Nakamura, Yoshimasa

AU - Koizumi, Fumito

AU - Ohigashi, Hajime

AU - Wender, Paul A.

AU - Satomi, Yoshiko

AU - Nishino, Hoyoku

PY - 1996/11/6

Y1 - 1996/11/6

N2 - The tumor-promoting teleocidins and their core structure (-)-indolactam-V (1) exist in two stable conformers in solution at room temperature. The cis amide assumes a twist conformation while the trans amide exists in a sofa form. In order to identify the biologically active conformation of the teleocidins, we have synthesized new twist-restricted analogues 5a and 6 based on an aza-Claisen rearrangement of (-)-N13-desmethyl-N13-allylindolactam-V (3) and a sofa-restricted analogue, (-)-5-methylindolactam-V (22). The activities of these new compounds were evaluated in three in vitro bioassays associated with in vivo tumor-promoting activity: binding to the protein kinase C regulatory domain, induction of the Epstein-Barr virus early antigen, and stimulation of radioactive inorganic phosphate incorporation into phospholipids of HeLa cells. These three biological activities correlated well for each derivative. Twist-restricted analogues 5a and 6 showed significant activities in the three assays, comparable to 1 itself. In contrast, sofa-restricted 22 showed little activity related to tumor promotion. Introduction of a prenyl group into position 7 or 18 of 5a and 6 significantly enhanced the activity while sofa-restricted (-)-5-prenylindolactam-V (23) showed only very weak activity. These results indicate that the active conformation of the teleocidins and 1 is close to the twist form. This is the first evidence bearing on the active conformation of the teleocidins based on conformationally restricted analogues with an intact indolactam skeleton and is in accord with conclusions reported for benzolactams, analogues without the pyrrole moiety. This study also describes the synthesis of new biologically active compounds (26a, 26b, 28) based on inactive (+)-epiindolactam-V (24), involving a further application of the aza-Claisen rearrangement. Bridge formation between positions 5 and 13 of indolactam derivatives represents a particularly effective analogue design strategy, allowing for the remote control of the conformation of this ring system and for the introduction of a wide range of structural variations, as required for the development of new protein kinase C activators with high isozyme selectivity.

AB - The tumor-promoting teleocidins and their core structure (-)-indolactam-V (1) exist in two stable conformers in solution at room temperature. The cis amide assumes a twist conformation while the trans amide exists in a sofa form. In order to identify the biologically active conformation of the teleocidins, we have synthesized new twist-restricted analogues 5a and 6 based on an aza-Claisen rearrangement of (-)-N13-desmethyl-N13-allylindolactam-V (3) and a sofa-restricted analogue, (-)-5-methylindolactam-V (22). The activities of these new compounds were evaluated in three in vitro bioassays associated with in vivo tumor-promoting activity: binding to the protein kinase C regulatory domain, induction of the Epstein-Barr virus early antigen, and stimulation of radioactive inorganic phosphate incorporation into phospholipids of HeLa cells. These three biological activities correlated well for each derivative. Twist-restricted analogues 5a and 6 showed significant activities in the three assays, comparable to 1 itself. In contrast, sofa-restricted 22 showed little activity related to tumor promotion. Introduction of a prenyl group into position 7 or 18 of 5a and 6 significantly enhanced the activity while sofa-restricted (-)-5-prenylindolactam-V (23) showed only very weak activity. These results indicate that the active conformation of the teleocidins and 1 is close to the twist form. This is the first evidence bearing on the active conformation of the teleocidins based on conformationally restricted analogues with an intact indolactam skeleton and is in accord with conclusions reported for benzolactams, analogues without the pyrrole moiety. This study also describes the synthesis of new biologically active compounds (26a, 26b, 28) based on inactive (+)-epiindolactam-V (24), involving a further application of the aza-Claisen rearrangement. Bridge formation between positions 5 and 13 of indolactam derivatives represents a particularly effective analogue design strategy, allowing for the remote control of the conformation of this ring system and for the introduction of a wide range of structural variations, as required for the development of new protein kinase C activators with high isozyme selectivity.

UR - http://www.scopus.com/inward/record.url?scp=10544240767&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=10544240767&partnerID=8YFLogxK

U2 - 10.1021/ja961727j

DO - 10.1021/ja961727j

M3 - Article

AN - SCOPUS:10544240767

VL - 118

SP - 10733

EP - 10743

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

SN - 0002-7863

IS - 44

ER -