Cytotoxic activities of Mannich bases of chalcones and related compounds

Jonathan R. Dimmock, N. Murthi Kandepu, Mark Hetherington, J. Wilson Quail, Uma Pugazhenthi, Athena M. Sudom, Mahmood Chamankhah, Patricia Rose, Eric Pass, Theresa M. Allen, Sarah Halleran, Jen Szydlowski, Bulent Mutus, Marie Tannous, Elias Kurian Manavathu, Timothy G. Myers, Erik De Clercq, Jan Balzarini

Research output: Contribution to journalArticle

159 Citations (Scopus)

Abstract

Various Mannich bases of chalcones and related compounds displayed significant cytotoxicity toward murine P388 and L1210 leukemia cells as well as a number of human tumor cell lines. The most promising lead molecule was 21 that had the highest activity toward L1210 and human tumor cells. In addition, 21 exerted preferential toxicity to human tumor lines compared to transformed human T-lymphocytes. Other compounds of interest were 38, with a huge differential in cytotoxicity between P388 and L1210 cells, and 42, with a high therapeutic index when cytotoxicity to P388 cells and Molt 4/C8 T- lymphocytes were compared. In general, the Mannich bases were more cytotoxic than the corresponding chalcones toward L1210 but not P388 cells. A ClusCor analysis of the data obtained from the in vitro human tumor screen revealed that the mode of action of certain groups of compounds was similar. For some groups of compounds, cytotoxicity was correlated with the δ, π, or molar refractivity constants in the aryl ring attached to the olefinic group. In addition, the IC50 values in all three screens correlated with the redox potentials of a number of Mannich bases. X-ray crystallography and molecular modeling of representative compounds revealed various structural features which were considered to contribute to cytotoxicity. While a representative compound 15 was stable and unreactive toward glutathione (GSH) in buffer, the Mannich bases 15, 18, and 21 reacted with GSH in the presence of the π isozyme of glutathione S-transferase, suggesting that thiol alkylation may be one mechanism by which cytotoxicity was exerted in vitro. Representative compounds were shown to be nonmutagenic in an intrachromosomal recombination assay in yeast, devoid of antimicrobial properties and possessing anticonvulsant and neurotoxic properties. Thus Mannich bases of chalcones represent a new group of cytotoxic agents of which 21 in particular serves as an useful prototypic molecule.

Original languageEnglish (US)
Pages (from-to)1014-1026
Number of pages13
JournalJournal of Medicinal Chemistry
Volume41
Issue number7
DOIs
StatePublished - Mar 26 1998

Fingerprint

Mannich Bases
Chalcones
Leukemia P388
T-Lymphocytes
Leukemia L1210
Neoplasms
X Ray Crystallography
Cytotoxins
Alkylation
Glutathione Transferase
Tumor Cell Line
Sulfhydryl Compounds
Anticonvulsants
Genetic Recombination
Isoenzymes
Inhibitory Concentration 50
Oxidation-Reduction
Glutathione
Buffers
Yeasts

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Dimmock, J. R., Murthi Kandepu, N., Hetherington, M., Wilson Quail, J., Pugazhenthi, U., Sudom, A. M., ... Balzarini, J. (1998). Cytotoxic activities of Mannich bases of chalcones and related compounds. Journal of Medicinal Chemistry, 41(7), 1014-1026. https://doi.org/10.1021/jm970432t

Cytotoxic activities of Mannich bases of chalcones and related compounds. / Dimmock, Jonathan R.; Murthi Kandepu, N.; Hetherington, Mark; Wilson Quail, J.; Pugazhenthi, Uma; Sudom, Athena M.; Chamankhah, Mahmood; Rose, Patricia; Pass, Eric; Allen, Theresa M.; Halleran, Sarah; Szydlowski, Jen; Mutus, Bulent; Tannous, Marie; Manavathu, Elias Kurian; Myers, Timothy G.; De Clercq, Erik; Balzarini, Jan.

In: Journal of Medicinal Chemistry, Vol. 41, No. 7, 26.03.1998, p. 1014-1026.

Research output: Contribution to journalArticle

Dimmock, JR, Murthi Kandepu, N, Hetherington, M, Wilson Quail, J, Pugazhenthi, U, Sudom, AM, Chamankhah, M, Rose, P, Pass, E, Allen, TM, Halleran, S, Szydlowski, J, Mutus, B, Tannous, M, Manavathu, EK, Myers, TG, De Clercq, E & Balzarini, J 1998, 'Cytotoxic activities of Mannich bases of chalcones and related compounds', Journal of Medicinal Chemistry, vol. 41, no. 7, pp. 1014-1026. https://doi.org/10.1021/jm970432t
Dimmock JR, Murthi Kandepu N, Hetherington M, Wilson Quail J, Pugazhenthi U, Sudom AM et al. Cytotoxic activities of Mannich bases of chalcones and related compounds. Journal of Medicinal Chemistry. 1998 Mar 26;41(7):1014-1026. https://doi.org/10.1021/jm970432t
Dimmock, Jonathan R. ; Murthi Kandepu, N. ; Hetherington, Mark ; Wilson Quail, J. ; Pugazhenthi, Uma ; Sudom, Athena M. ; Chamankhah, Mahmood ; Rose, Patricia ; Pass, Eric ; Allen, Theresa M. ; Halleran, Sarah ; Szydlowski, Jen ; Mutus, Bulent ; Tannous, Marie ; Manavathu, Elias Kurian ; Myers, Timothy G. ; De Clercq, Erik ; Balzarini, Jan. / Cytotoxic activities of Mannich bases of chalcones and related compounds. In: Journal of Medicinal Chemistry. 1998 ; Vol. 41, No. 7. pp. 1014-1026.
@article{18913e6696594f28853174dc18a92741,
title = "Cytotoxic activities of Mannich bases of chalcones and related compounds",
abstract = "Various Mannich bases of chalcones and related compounds displayed significant cytotoxicity toward murine P388 and L1210 leukemia cells as well as a number of human tumor cell lines. The most promising lead molecule was 21 that had the highest activity toward L1210 and human tumor cells. In addition, 21 exerted preferential toxicity to human tumor lines compared to transformed human T-lymphocytes. Other compounds of interest were 38, with a huge differential in cytotoxicity between P388 and L1210 cells, and 42, with a high therapeutic index when cytotoxicity to P388 cells and Molt 4/C8 T- lymphocytes were compared. In general, the Mannich bases were more cytotoxic than the corresponding chalcones toward L1210 but not P388 cells. A ClusCor analysis of the data obtained from the in vitro human tumor screen revealed that the mode of action of certain groups of compounds was similar. For some groups of compounds, cytotoxicity was correlated with the δ, π, or molar refractivity constants in the aryl ring attached to the olefinic group. In addition, the IC50 values in all three screens correlated with the redox potentials of a number of Mannich bases. X-ray crystallography and molecular modeling of representative compounds revealed various structural features which were considered to contribute to cytotoxicity. While a representative compound 15 was stable and unreactive toward glutathione (GSH) in buffer, the Mannich bases 15, 18, and 21 reacted with GSH in the presence of the π isozyme of glutathione S-transferase, suggesting that thiol alkylation may be one mechanism by which cytotoxicity was exerted in vitro. Representative compounds were shown to be nonmutagenic in an intrachromosomal recombination assay in yeast, devoid of antimicrobial properties and possessing anticonvulsant and neurotoxic properties. Thus Mannich bases of chalcones represent a new group of cytotoxic agents of which 21 in particular serves as an useful prototypic molecule.",
author = "Dimmock, {Jonathan R.} and {Murthi Kandepu}, N. and Mark Hetherington and {Wilson Quail}, J. and Uma Pugazhenthi and Sudom, {Athena M.} and Mahmood Chamankhah and Patricia Rose and Eric Pass and Allen, {Theresa M.} and Sarah Halleran and Jen Szydlowski and Bulent Mutus and Marie Tannous and Manavathu, {Elias Kurian} and Myers, {Timothy G.} and {De Clercq}, Erik and Jan Balzarini",
year = "1998",
month = "3",
day = "26",
doi = "10.1021/jm970432t",
language = "English (US)",
volume = "41",
pages = "1014--1026",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "7",

}

TY - JOUR

T1 - Cytotoxic activities of Mannich bases of chalcones and related compounds

AU - Dimmock, Jonathan R.

AU - Murthi Kandepu, N.

AU - Hetherington, Mark

AU - Wilson Quail, J.

AU - Pugazhenthi, Uma

AU - Sudom, Athena M.

AU - Chamankhah, Mahmood

AU - Rose, Patricia

AU - Pass, Eric

AU - Allen, Theresa M.

AU - Halleran, Sarah

AU - Szydlowski, Jen

AU - Mutus, Bulent

AU - Tannous, Marie

AU - Manavathu, Elias Kurian

AU - Myers, Timothy G.

AU - De Clercq, Erik

AU - Balzarini, Jan

PY - 1998/3/26

Y1 - 1998/3/26

N2 - Various Mannich bases of chalcones and related compounds displayed significant cytotoxicity toward murine P388 and L1210 leukemia cells as well as a number of human tumor cell lines. The most promising lead molecule was 21 that had the highest activity toward L1210 and human tumor cells. In addition, 21 exerted preferential toxicity to human tumor lines compared to transformed human T-lymphocytes. Other compounds of interest were 38, with a huge differential in cytotoxicity between P388 and L1210 cells, and 42, with a high therapeutic index when cytotoxicity to P388 cells and Molt 4/C8 T- lymphocytes were compared. In general, the Mannich bases were more cytotoxic than the corresponding chalcones toward L1210 but not P388 cells. A ClusCor analysis of the data obtained from the in vitro human tumor screen revealed that the mode of action of certain groups of compounds was similar. For some groups of compounds, cytotoxicity was correlated with the δ, π, or molar refractivity constants in the aryl ring attached to the olefinic group. In addition, the IC50 values in all three screens correlated with the redox potentials of a number of Mannich bases. X-ray crystallography and molecular modeling of representative compounds revealed various structural features which were considered to contribute to cytotoxicity. While a representative compound 15 was stable and unreactive toward glutathione (GSH) in buffer, the Mannich bases 15, 18, and 21 reacted with GSH in the presence of the π isozyme of glutathione S-transferase, suggesting that thiol alkylation may be one mechanism by which cytotoxicity was exerted in vitro. Representative compounds were shown to be nonmutagenic in an intrachromosomal recombination assay in yeast, devoid of antimicrobial properties and possessing anticonvulsant and neurotoxic properties. Thus Mannich bases of chalcones represent a new group of cytotoxic agents of which 21 in particular serves as an useful prototypic molecule.

AB - Various Mannich bases of chalcones and related compounds displayed significant cytotoxicity toward murine P388 and L1210 leukemia cells as well as a number of human tumor cell lines. The most promising lead molecule was 21 that had the highest activity toward L1210 and human tumor cells. In addition, 21 exerted preferential toxicity to human tumor lines compared to transformed human T-lymphocytes. Other compounds of interest were 38, with a huge differential in cytotoxicity between P388 and L1210 cells, and 42, with a high therapeutic index when cytotoxicity to P388 cells and Molt 4/C8 T- lymphocytes were compared. In general, the Mannich bases were more cytotoxic than the corresponding chalcones toward L1210 but not P388 cells. A ClusCor analysis of the data obtained from the in vitro human tumor screen revealed that the mode of action of certain groups of compounds was similar. For some groups of compounds, cytotoxicity was correlated with the δ, π, or molar refractivity constants in the aryl ring attached to the olefinic group. In addition, the IC50 values in all three screens correlated with the redox potentials of a number of Mannich bases. X-ray crystallography and molecular modeling of representative compounds revealed various structural features which were considered to contribute to cytotoxicity. While a representative compound 15 was stable and unreactive toward glutathione (GSH) in buffer, the Mannich bases 15, 18, and 21 reacted with GSH in the presence of the π isozyme of glutathione S-transferase, suggesting that thiol alkylation may be one mechanism by which cytotoxicity was exerted in vitro. Representative compounds were shown to be nonmutagenic in an intrachromosomal recombination assay in yeast, devoid of antimicrobial properties and possessing anticonvulsant and neurotoxic properties. Thus Mannich bases of chalcones represent a new group of cytotoxic agents of which 21 in particular serves as an useful prototypic molecule.

UR - http://www.scopus.com/inward/record.url?scp=15144357004&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=15144357004&partnerID=8YFLogxK

U2 - 10.1021/jm970432t

DO - 10.1021/jm970432t

M3 - Article

C2 - 9544201

AN - SCOPUS:15144357004

VL - 41

SP - 1014

EP - 1026

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 7

ER -