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Modification of the...
Modification of the anticancer drug tamoxifen to avoid CYP2D6 polymorphism
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- Gao, Li (författare)
- KTH,Teoretisk kemi och biologi
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- Sun, Xianqiang (författare)
- KTH,Teoretisk kemi och biologi
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- Tu, Yaoquan (författare)
- KTH,Teoretisk kemi och biologi
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- Ågren, Hans (författare)
- KTH,Teoretisk kemi och biologi
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- Eriksson, Leif A, 1964 (författare)
- Gothenburg University,Göteborgs universitet,Institutionen för kemi och molekylärbiologi,Department of Chemistry and Molecular Biology
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(creator_code:org_t)
- Canadian Science Publishing, 2013
- 2013
- Engelska.
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Ingår i: Canadian Journal of Chemistry-Revue Canadienne De Chimie. - : Canadian Science Publishing. - 0008-4042 .- 1480-3291. ; 91:9, s. 916-924
- Relaterad länk:
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https://gup.ub.gu.se...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- The prodrug tamoxifen (TAM) is the most widely used drug to treat breast cancer, and is metabolised to the active 4-hydroxy derivatives dominantly by hepatic CYP2D6. However, the application to patients with different polymorphic CYP2D6 has been under debate, because the efficacy of TAM is suspected to be suppressed in patients who have diminished CYP2D6 activity, resulting in inadequate active metabolites. We here propose modified structures, such as 4-methylTAM, which is highly possible to be activated by CYP3A, the most abundant CYP isoforms in the liver, whereby the genetic polymorphism of CYP2D6 is avoided. The diversity of CYP catalyzed metabolic paths for TAM and its derivatives are studied by quantum chemistry calculations on the reaction energies of the initial H atom abstraction steps. The ability of forming DNA adducts is compared through the formation enthalpy of the carbocation intermediate. The results suggest that the modified structures are safe with regard to forming DNA adducts and may be used as prodrugs in a wide range of patients, due to CYP3A, rather than CYP2D6, mediated activation.
Ämnesord
- NATURVETENSKAP -- Kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences (hsv//eng)
- NATURVETENSKAP -- Kemi -- Annan kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences -- Other Chemistry Topics (hsv//eng)
Nyckelord
- SERM
- cytochrome P450
- DNA adducts
- hydroxylation
- dealkylation
- BREAST-CANCER PATIENTS
- DNA ADDUCT FORMATION
- RECEIVING ADJUVANT
- TAMOXIFEN
- CYTOCHROME-P450 ENZYMES
- FORCE-FIELD
- ANISOTROPIC
- DIELECTRICS
- MECHANISTIC HYPOTHESIS
- DENSITY FUNCTIONALS
- RECEPTOR
- MODULATORS
- ESTROGEN-RECEPTOR
- SERM
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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