Date post: | 03-Jan-2016 |
Category: |
Documents |
Upload: | jodie-audra-andrews |
View: | 214 times |
Download: | 0 times |
Outline
Introduction Malaria Artemisinin
Rationale for Research Modes of Action
Iron-Oxo route Epoxidation reactions Alkylation reactions
The Target of Artemisinin
Introduction
Malaria Four species of
Plasmodium Infects 200 million
people annually 1 million lethal Resistance to current
drugs
Introduction
Artemisinin Natural product
extracted from sweet wormwood, Artemisia annua
Used by Chinese for over 2000 years
A. absinthium used to make absinthe
Rationale for Research
Anti-malarial Activity of Artemisinin Artemisinin Derivatives
Used currently for life threatening cases
Rationale for Research
Anti-malarial Activity of Artemisinin Artemisinin Derivatives
• Used currently for life threatening cases Drug Resistance of Plasmodium
• Malaria spreading• Synthesis of new drugs
Iron-Oxo Route
Donation of Oxygen from Peroxide Bridge to Iron Generate Fe(IV)=O
No Support from Raman Resonance Data Signal/Noise < 2 Should be ~10 or 20
Epoxidation Reactions
+ ARTEMISININ NO EPOXIDE FORMATION
O
MnIITPP or FeCl2
+
ORMnIITPP or FeCl2 EPOXIDE FORMATION
NH
NN
HN
Ph
PhPh
Ph
MnII
Fe
ClCl
Na+ -OCl
1,5 H Shift Possible???
Critical Distance Calculated to be 2.1Å
Exceeded in Stable Conformation
Boat-like Conformation (High energy state) Houk
Comparing Route 1 and 2
Route 1 Dominant to Route 2 90/10 ratio from isolated products
Artemisinin + MnIITPP 1,5 H shift?
Route 1 Biologically Active Route 2 Inactive Stereochemistry Effecting Alkylation
Mode of Action
Route 1 Dominant Alkyl radical formation
from reduction of peroxide bridge
Derivatives Used Observe correlation of
alkylating ability to drug activity
Alkylate MnIITPP Pharm. active
The Target
Alkylation of Heme within Infected Erythrocytes (RBC’s) Free heme in food vacuole of erythrocyte Cleavage of peroxide bond Alkylation of heme or specific parasite proteins
can occur Too General…
The Target, More Specifically
Sarco/Endoplasmic Reticulum Ca2+-ATPase (SERCA) Enzyme PfATP6 gene sequence Testing the hypothesis
Heme Not Required? Free heme blocked with Ro 40-4388 protease
inhibitor Localized in the Food Vacuole?
Fluorescent labeled artemisinin
Conclusions
Malaria Remains as a Problem Resistant strains
Anti-malarial Activity of Artemisinin Mode of Action is Now Understood
Alkylation via route 1 A Specific Target Found
PfATP6 gene sequence of the SERCA enzyme
Fe2+ is required Activity not localized in the food vacuole
References
1. Robert, Anne, et al. “From Mechanistic Studies on Artemisinin Derivatives to New Modular Antimalarial Drugs.” Accounts of Chemical Research, 2002, Vol. 35, pp. 167-174.
2. Cazelles, Jerome, et al. “Alkylating Capacity and Reaction Products of Antimalarial Trioxanes after Activation by a Heme Model.” The Journal of Organic Chemistry, 2002, Vol. 67, Number 3, pp. 609-619.
3. Wu, Wen-Min, et al. “Unified Mechanistic Framework for the Fe(II)-Induced Cleavage of Qinghaosu and Derivatives/Analogues. The First Spin-Trapping Evidence for the Previously Postulated Secondary C-4 Radical.” J. Am. Chem. Soc., 1998, Vol. 120, pp. 3316-3325.
4. Biot, Christophe, et al. “Synthesis and Antimalarial Activity in Vitro and in Vivo of a New Ferrocene-Chloroquine Analogue.” J. of Medicinal Chemistry, 1997, Vol. 40, pp. 3715-3718.
5. Yarnell, Amanda; “Rethinking How Artemisinin Kills,” Chemical and Engineering News, Aug. 25, 2003, Vol. 81 (24), pp. 6.
6. Eckstein-Ludwig, Ursula, et al. “Artemisinins Target the SERCA of Plasmodium falciparum,” Nature, 2003, Vol. 424, pp.957.