Derivatization of agelastatin A leading to bioactive analogs and a trifunctional probe

Morgan Jouanneau, Brandon McClary, Jeremy Chris P. Reyes, Rong Chen, Yuling Chen, William K Plunkett Jr, Xin Cheng, Andrew Z. Milinichik, Earl F. Albone, Jun O. Liu, Daniel Romo

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

(-)-Agelastatin A (AglA, 1), a member of the pyrrole-aminoimidazole marine alkaloid (PAI) family, possesses a unique tetracyclic structure and is one of the most potent anticancer PAIs isolated to date. In efforts to expand the SAR of these agents and delineate sites that tolerate modification while retaining activity, we synthesized several derivatives and tested their anticancer activity. The cytotoxic effects of these derivatives were measured against several cancer cell lines including cervical cancer (HeLa), epidermoid carcinoma (A431), ovarian (Igrov and Ovcar3), osteosarcoma (SJSA1), acute T cell leukemia (A3), epidermoid carcinoma (A431) in addition to primary human chronic lymphocytic leukemia (CLL) cells. New positions for modification of AglA and new substitutions were explored leading to novel derivatives, 14-chloro AglA (3) and 14-methyl AglA (12), that retained activity toward various cancer cell lines with decreased toxicity toward B- and T-cells. The SAR data informed the synthesis of a trifunctional probe bearing an alkyne and a diazirine potentially useful for cellular target identification.

Original languageEnglish (US)
Pages (from-to)2092-2097
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume26
Issue number8
DOIs
StatePublished - Apr 15 2016

Fingerprint

Squamous Cell Carcinoma
T-cells
Diazomethane
Derivatives
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Cell Line
Pyrroles
Alkynes
Osteosarcoma
Bearings (structural)
B-Cell Chronic Lymphocytic Leukemia
Cells
Alkaloids
Polyamideimides
Uterine Cervical Neoplasms
Neoplasms
T-Lymphocytes
Toxicity
Substitution reactions
agelastatin A

Keywords

  • Agelastatin A
  • Diazirine
  • Photoaffinity probe
  • Pyrrole-aminoimidazole alkaloid
  • Structure-activity relationship

ASJC Scopus subject areas

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

Cite this

Derivatization of agelastatin A leading to bioactive analogs and a trifunctional probe. / Jouanneau, Morgan; McClary, Brandon; Reyes, Jeremy Chris P.; Chen, Rong; Chen, Yuling; Plunkett Jr, William K; Cheng, Xin; Milinichik, Andrew Z.; Albone, Earl F.; Liu, Jun O.; Romo, Daniel.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 26, No. 8, 15.04.2016, p. 2092-2097.

Research output: Contribution to journalArticle

Jouanneau, M, McClary, B, Reyes, JCP, Chen, R, Chen, Y, Plunkett Jr, WK, Cheng, X, Milinichik, AZ, Albone, EF, Liu, JO & Romo, D 2016, 'Derivatization of agelastatin A leading to bioactive analogs and a trifunctional probe', Bioorganic and Medicinal Chemistry Letters, vol. 26, no. 8, pp. 2092-2097. https://doi.org/10.1016/j.bmcl.2016.02.051
Jouanneau, Morgan ; McClary, Brandon ; Reyes, Jeremy Chris P. ; Chen, Rong ; Chen, Yuling ; Plunkett Jr, William K ; Cheng, Xin ; Milinichik, Andrew Z. ; Albone, Earl F. ; Liu, Jun O. ; Romo, Daniel. / Derivatization of agelastatin A leading to bioactive analogs and a trifunctional probe. In: Bioorganic and Medicinal Chemistry Letters. 2016 ; Vol. 26, No. 8. pp. 2092-2097.
@article{16297f5dffa245f080fdb20f87787e1f,
title = "Derivatization of agelastatin A leading to bioactive analogs and a trifunctional probe",
abstract = "(-)-Agelastatin A (AglA, 1), a member of the pyrrole-aminoimidazole marine alkaloid (PAI) family, possesses a unique tetracyclic structure and is one of the most potent anticancer PAIs isolated to date. In efforts to expand the SAR of these agents and delineate sites that tolerate modification while retaining activity, we synthesized several derivatives and tested their anticancer activity. The cytotoxic effects of these derivatives were measured against several cancer cell lines including cervical cancer (HeLa), epidermoid carcinoma (A431), ovarian (Igrov and Ovcar3), osteosarcoma (SJSA1), acute T cell leukemia (A3), epidermoid carcinoma (A431) in addition to primary human chronic lymphocytic leukemia (CLL) cells. New positions for modification of AglA and new substitutions were explored leading to novel derivatives, 14-chloro AglA (3) and 14-methyl AglA (12), that retained activity toward various cancer cell lines with decreased toxicity toward B- and T-cells. The SAR data informed the synthesis of a trifunctional probe bearing an alkyne and a diazirine potentially useful for cellular target identification.",
keywords = "Agelastatin A, Diazirine, Photoaffinity probe, Pyrrole-aminoimidazole alkaloid, Structure-activity relationship",
author = "Morgan Jouanneau and Brandon McClary and Reyes, {Jeremy Chris P.} and Rong Chen and Yuling Chen and {Plunkett Jr}, {William K} and Xin Cheng and Milinichik, {Andrew Z.} and Albone, {Earl F.} and Liu, {Jun O.} and Daniel Romo",
year = "2016",
month = "4",
day = "15",
doi = "10.1016/j.bmcl.2016.02.051",
language = "English (US)",
volume = "26",
pages = "2092--2097",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "8",

}

TY - JOUR

T1 - Derivatization of agelastatin A leading to bioactive analogs and a trifunctional probe

AU - Jouanneau, Morgan

AU - McClary, Brandon

AU - Reyes, Jeremy Chris P.

AU - Chen, Rong

AU - Chen, Yuling

AU - Plunkett Jr, William K

AU - Cheng, Xin

AU - Milinichik, Andrew Z.

AU - Albone, Earl F.

AU - Liu, Jun O.

AU - Romo, Daniel

PY - 2016/4/15

Y1 - 2016/4/15

N2 - (-)-Agelastatin A (AglA, 1), a member of the pyrrole-aminoimidazole marine alkaloid (PAI) family, possesses a unique tetracyclic structure and is one of the most potent anticancer PAIs isolated to date. In efforts to expand the SAR of these agents and delineate sites that tolerate modification while retaining activity, we synthesized several derivatives and tested their anticancer activity. The cytotoxic effects of these derivatives were measured against several cancer cell lines including cervical cancer (HeLa), epidermoid carcinoma (A431), ovarian (Igrov and Ovcar3), osteosarcoma (SJSA1), acute T cell leukemia (A3), epidermoid carcinoma (A431) in addition to primary human chronic lymphocytic leukemia (CLL) cells. New positions for modification of AglA and new substitutions were explored leading to novel derivatives, 14-chloro AglA (3) and 14-methyl AglA (12), that retained activity toward various cancer cell lines with decreased toxicity toward B- and T-cells. The SAR data informed the synthesis of a trifunctional probe bearing an alkyne and a diazirine potentially useful for cellular target identification.

AB - (-)-Agelastatin A (AglA, 1), a member of the pyrrole-aminoimidazole marine alkaloid (PAI) family, possesses a unique tetracyclic structure and is one of the most potent anticancer PAIs isolated to date. In efforts to expand the SAR of these agents and delineate sites that tolerate modification while retaining activity, we synthesized several derivatives and tested their anticancer activity. The cytotoxic effects of these derivatives were measured against several cancer cell lines including cervical cancer (HeLa), epidermoid carcinoma (A431), ovarian (Igrov and Ovcar3), osteosarcoma (SJSA1), acute T cell leukemia (A3), epidermoid carcinoma (A431) in addition to primary human chronic lymphocytic leukemia (CLL) cells. New positions for modification of AglA and new substitutions were explored leading to novel derivatives, 14-chloro AglA (3) and 14-methyl AglA (12), that retained activity toward various cancer cell lines with decreased toxicity toward B- and T-cells. The SAR data informed the synthesis of a trifunctional probe bearing an alkyne and a diazirine potentially useful for cellular target identification.

KW - Agelastatin A

KW - Diazirine

KW - Photoaffinity probe

KW - Pyrrole-aminoimidazole alkaloid

KW - Structure-activity relationship

UR - http://www.scopus.com/inward/record.url?scp=84959459130&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84959459130&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2016.02.051

DO - 10.1016/j.bmcl.2016.02.051

M3 - Article

C2 - 26951751

AN - SCOPUS:84959459130

VL - 26

SP - 2092

EP - 2097

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 8

ER -