Bimane cyclic esters, possible stereologues of trypanothione as antitrypanosomal agents. Bimanes 29

EM M. Kosower; AE E. Radkowsky; AH H. Fairlamb; SL L. Croft; RA A. Neal

doi:10.1016/0223-5234(96)88283-3

Bimane cyclic esters, possible stereologues of trypanothione as antitrypanosomal agents. Bimanes 29

EM M. Kosower, AE E. Radkowsky, AH H. Fairlamb, SL L. Croft, RA A. Neal

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

66 Citations (Scopus)

Abstract

Tricyclic esters derived from bimanes have been synthesized with ring sizes near or equal to that of trypanothione disulfide (T(S)₂), a bis-glutathionylspermidine that is involved in regulating the thiol status of Leishmania and other trypanosomatids. Modest activity for many of the compounds against Leishmania donovani with a maximum at the T(S)₂ ring size suggests that the esters act as T(S)₂ surrogates. However, no inhibition of T(S)₂-reductase is observed for a number of the compounds. A series of tricyclic bimane amides with structures more closely analogous to T(S)₂ are inactive in biological tests. New approaches were developed for the synthesis of the amides. The surprising effectiveness of the cyclic ester synthesis is explained. Acid chloride formation catalyzed by sulfides is briefly described.

Original language	English
Pages (from-to)	659-671
Number of pages	13
Journal	European Journal of Medicinal Chemistry
Volume	30
Issue number	9
DOIs	https://doi.org/10.1016/0223-5234(96)88283-3
Publication status	Published - 1995

Keywords

acid chloride formation
antitrypanosomal drug
bimane ester
DFMO
dl-α-difluoromethylornithine
glutathione
glutathione disulfide
GSH
GSSG
reduced trypanothione
sulfide catalysis
T(S)
T(SH)
trypanothione
trypanothione stereologue

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/0223-5234(96)88283-3

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title = "Bimane cyclic esters, possible stereologues of trypanothione as antitrypanosomal agents. Bimanes 29",

abstract = "Tricyclic esters derived from bimanes have been synthesized with ring sizes near or equal to that of trypanothione disulfide (T(S)2), a bis-glutathionylspermidine that is involved in regulating the thiol status of Leishmania and other trypanosomatids. Modest activity for many of the compounds against Leishmania donovani with a maximum at the T(S)2 ring size suggests that the esters act as T(S)2 surrogates. However, no inhibition of T(S)2-reductase is observed for a number of the compounds. A series of tricyclic bimane amides with structures more closely analogous to T(S)2 are inactive in biological tests. New approaches were developed for the synthesis of the amides. The surprising effectiveness of the cyclic ester synthesis is explained. Acid chloride formation catalyzed by sulfides is briefly described.",

keywords = "acid chloride formation, antitrypanosomal drug, bimane ester, DFMO, dl-α-difluoromethylornithine, glutathione, glutathione disulfide, GSH, GSSG, reduced trypanothione, sulfide catalysis, T(S), T(SH), trypanothione, trypanothione stereologue",

author = "Kosower, {EM M.} and Radkowsky, {AE E.} and Fairlamb, {AH H.} and Croft, {SL L.} and Neal, {RA A.}",

note = "Funding Information: Wellcome Trust through a grant to the University of London is much appreciated. The investigation also received financial support from the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases. We appreciate the cooperation of L Krauth-Siegel, Institut fur Biochemie II, Medizinische Fakultlt, Universitat Heidelberg, Germany, in carrying out the tests of inhibition of T cruzi trypanothione reductase.",

year = "1995",

doi = "10.1016/0223-5234(96)88283-3",

language = "English",

volume = "30",

pages = "659--671",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier",

number = "9",

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TY - JOUR

T1 - Bimane cyclic esters, possible stereologues of trypanothione as antitrypanosomal agents. Bimanes 29

AU - Kosower, EM M.

AU - Radkowsky, AE E.

AU - Fairlamb, AH H.

AU - Croft, SL L.

AU - Neal, RA A.

N1 - Funding Information: Wellcome Trust through a grant to the University of London is much appreciated. The investigation also received financial support from the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases. We appreciate the cooperation of L Krauth-Siegel, Institut fur Biochemie II, Medizinische Fakultlt, Universitat Heidelberg, Germany, in carrying out the tests of inhibition of T cruzi trypanothione reductase.

PY - 1995

Y1 - 1995

N2 - Tricyclic esters derived from bimanes have been synthesized with ring sizes near or equal to that of trypanothione disulfide (T(S)2), a bis-glutathionylspermidine that is involved in regulating the thiol status of Leishmania and other trypanosomatids. Modest activity for many of the compounds against Leishmania donovani with a maximum at the T(S)2 ring size suggests that the esters act as T(S)2 surrogates. However, no inhibition of T(S)2-reductase is observed for a number of the compounds. A series of tricyclic bimane amides with structures more closely analogous to T(S)2 are inactive in biological tests. New approaches were developed for the synthesis of the amides. The surprising effectiveness of the cyclic ester synthesis is explained. Acid chloride formation catalyzed by sulfides is briefly described.

AB - Tricyclic esters derived from bimanes have been synthesized with ring sizes near or equal to that of trypanothione disulfide (T(S)2), a bis-glutathionylspermidine that is involved in regulating the thiol status of Leishmania and other trypanosomatids. Modest activity for many of the compounds against Leishmania donovani with a maximum at the T(S)2 ring size suggests that the esters act as T(S)2 surrogates. However, no inhibition of T(S)2-reductase is observed for a number of the compounds. A series of tricyclic bimane amides with structures more closely analogous to T(S)2 are inactive in biological tests. New approaches were developed for the synthesis of the amides. The surprising effectiveness of the cyclic ester synthesis is explained. Acid chloride formation catalyzed by sulfides is briefly described.

KW - acid chloride formation

KW - antitrypanosomal drug

KW - bimane ester

KW - DFMO

KW - dl-α-difluoromethylornithine

KW - glutathione

KW - glutathione disulfide

KW - GSH

KW - GSSG

KW - reduced trypanothione

KW - sulfide catalysis

KW - T(S)

KW - T(SH)

KW - trypanothione

KW - trypanothione stereologue

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U2 - 10.1016/0223-5234(96)88283-3

DO - 10.1016/0223-5234(96)88283-3

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SN - 0223-5234

VL - 30

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EP - 671

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

IS - 9

ER -

Bimane cyclic esters, possible stereologues of trypanothione as antitrypanosomal agents. Bimanes 29

Abstract

Keywords

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