Endoperoxide carbonyl falcipain 2/3 inhibitor hybrids: Toward combination chemotherapy of malaria through a single chemical entity

Peter Gibbons; Edite Verissimo; Nuna C. Araujo; Victoria Barton; Gemma L. Nixon; Richard K. Amewu; James Chadwick; Paul A. Stocks; Giancarlo A. Biagini; Abhishek Srivastava; Philip J. Rosenthal; Jiri Gut; Rita C. Guedes; Rui Moreira; Raman Sharma; Neil Berry; M. Lurdes S. Cristiano; Alison E. Shone; Stephen A. Ward; Paul M. O'Neill

doi:10.1021/jm1009567

Endoperoxide carbonyl falcipain 2/3 inhibitor hybrids: Toward combination chemotherapy of malaria through a single chemical entity

Peter Gibbons, Edite Verissimo, Nuna C. Araujo, Victoria Barton, Gemma L. Nixon, Richard K. Amewu, James Chadwick, Paul A. Stocks, Giancarlo A. Biagini, Abhishek Srivastava, Philip J. Rosenthal, Jiri Gut, Rita C. Guedes, Rui Moreira, Raman Sharma, Neil Berry, M. Lurdes S. Cristiano, Alison E. Shone, Stephen A. Ward, Paul M. O'Neill

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

36 Citations (Scopus)

Abstract

We extend our approach of combination chemotherapy through a single prodrug entity (O'Neill et al. Angew. Chem., Int. Ed. 2004, 43, 4193) by using a 1,2,4-trioxolane as a protease inhibitor carbonyl-masking group. These molecules are designed to target the malaria parasite through two independent mechanisms of action: iron(II) decomposition releases the carbonyl protease inhibitor and potentially cytotoxic C-radical species in tandem. Using a proposed target "heme", we also demonstrate heme alkylation/carbonyl inhibitor release and quantitatively measure endoperoxide turnover in parasitized red blood cells.

Original language	English
Pages (from-to)	8202-8206
Number of pages	5
Journal	Journal of Medicinal Chemistry
Volume	53
Issue number	22
DOIs	https://doi.org/10.1021/jm1009567
Publication status	Published - 25 Nov 2010
Externally published	Yes

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Gibbons, P., Verissimo, E., Araujo, N. C., Barton, V., Nixon, G. L., Amewu, R. K., Chadwick, J., Stocks, P. A., Biagini, G. A., Srivastava, A., Rosenthal, P. J., Gut, J., Guedes, R. C., Moreira, R., Sharma, R., Berry, N., Cristiano, M. L. S., Shone, A. E., Ward, S. A., & O'Neill, P. M. (2010). Endoperoxide carbonyl falcipain 2/3 inhibitor hybrids: Toward combination chemotherapy of malaria through a single chemical entity. Journal of Medicinal Chemistry, 53(22), 8202-8206. https://doi.org/10.1021/jm1009567

@article{23b8923c45b94b9da3e05c2b7341ef36,

title = "Endoperoxide carbonyl falcipain 2/3 inhibitor hybrids: Toward combination chemotherapy of malaria through a single chemical entity",

abstract = "We extend our approach of combination chemotherapy through a single prodrug entity (O'Neill et al. Angew. Chem., Int. Ed. 2004, 43, 4193) by using a 1,2,4-trioxolane as a protease inhibitor carbonyl-masking group. These molecules are designed to target the malaria parasite through two independent mechanisms of action: iron(II) decomposition releases the carbonyl protease inhibitor and potentially cytotoxic C-radical species in tandem. Using a proposed target {"}heme{"}, we also demonstrate heme alkylation/carbonyl inhibitor release and quantitatively measure endoperoxide turnover in parasitized red blood cells.",

author = "Peter Gibbons and Edite Verissimo and Araujo, {Nuna C.} and Victoria Barton and Nixon, {Gemma L.} and Amewu, {Richard K.} and James Chadwick and Stocks, {Paul A.} and Biagini, {Giancarlo A.} and Abhishek Srivastava and Rosenthal, {Philip J.} and Jiri Gut and Guedes, {Rita C.} and Rui Moreira and Raman Sharma and Neil Berry and Cristiano, {M. Lurdes S.} and Shone, {Alison E.} and Ward, {Stephen A.} and O'Neill, {Paul M.}",

year = "2010",

month = nov,

day = "25",

doi = "10.1021/jm1009567",

language = "English",

volume = "53",

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Gibbons, P, Verissimo, E, Araujo, NC, Barton, V, Nixon, GL, Amewu, RK, Chadwick, J, Stocks, PA, Biagini, GA, Srivastava, A, Rosenthal, PJ, Gut, J, Guedes, RC, Moreira, R, Sharma, R, Berry, N, Cristiano, MLS, Shone, AE, Ward, SA & O'Neill, PM 2010, 'Endoperoxide carbonyl falcipain 2/3 inhibitor hybrids: Toward combination chemotherapy of malaria through a single chemical entity', Journal of Medicinal Chemistry, vol. 53, no. 22, pp. 8202-8206. https://doi.org/10.1021/jm1009567

TY - JOUR

T1 - Endoperoxide carbonyl falcipain 2/3 inhibitor hybrids

T2 - Toward combination chemotherapy of malaria through a single chemical entity

AU - Gibbons, Peter

AU - Verissimo, Edite

AU - Araujo, Nuna C.

AU - Barton, Victoria

AU - Nixon, Gemma L.

AU - Amewu, Richard K.

AU - Chadwick, James

AU - Stocks, Paul A.

AU - Biagini, Giancarlo A.

AU - Srivastava, Abhishek

AU - Rosenthal, Philip J.

AU - Gut, Jiri

AU - Guedes, Rita C.

AU - Moreira, Rui

AU - Sharma, Raman

AU - Berry, Neil

AU - Cristiano, M. Lurdes S.

AU - Shone, Alison E.

AU - Ward, Stephen A.

AU - O'Neill, Paul M.

PY - 2010/11/25

Y1 - 2010/11/25

N2 - We extend our approach of combination chemotherapy through a single prodrug entity (O'Neill et al. Angew. Chem., Int. Ed. 2004, 43, 4193) by using a 1,2,4-trioxolane as a protease inhibitor carbonyl-masking group. These molecules are designed to target the malaria parasite through two independent mechanisms of action: iron(II) decomposition releases the carbonyl protease inhibitor and potentially cytotoxic C-radical species in tandem. Using a proposed target "heme", we also demonstrate heme alkylation/carbonyl inhibitor release and quantitatively measure endoperoxide turnover in parasitized red blood cells.

AB - We extend our approach of combination chemotherapy through a single prodrug entity (O'Neill et al. Angew. Chem., Int. Ed. 2004, 43, 4193) by using a 1,2,4-trioxolane as a protease inhibitor carbonyl-masking group. These molecules are designed to target the malaria parasite through two independent mechanisms of action: iron(II) decomposition releases the carbonyl protease inhibitor and potentially cytotoxic C-radical species in tandem. Using a proposed target "heme", we also demonstrate heme alkylation/carbonyl inhibitor release and quantitatively measure endoperoxide turnover in parasitized red blood cells.

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DO - 10.1021/jm1009567

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AN - SCOPUS:78649526279

SN - 0022-2623

VL - 53

SP - 8202

EP - 8206

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 22

ER -

Endoperoxide carbonyl falcipain 2/3 inhibitor hybrids: Toward combination chemotherapy of malaria through a single chemical entity

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