preparation and bioactivities of artemisinin derivatives

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• preparation and bioactivities of artemisinin
  derivatives
• .

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• Ahmed M. Galal,a Waseem Gul,b,c Desmond Slade,c
  Samir A. Ross, c,d Shaxia Feng,b Melinda G.
  Hollingsheade and Micheal C. Alleye and Mahmoud
  A. ElSohly b,c,f
• aCollege of Pharmacy, King Saud University,
  Riyadh, 11451, Saudi Arabia
• bElSohly Laboratories, Inc., 5 Industrial Park
  Drive, Oxford, MS 38655, USA
• cNational Center for Natural Products Research,
  School of Pharmacy, The University of
  Mississippi, University, MS 38677, USA
• dDepartment of Pharmacognosy, School of Pharmacy,
  The University of Mississippi, University, MS,
  38677,USA
• eDevelopmental Therapeutics Program, NCI,
  Frederick and Rockville, MD USA
• F Department of Pharmaceutics, School of
  Pharmacy, The University of Mississippi,
  University, MS 38677, USA

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• Artemisinin is a sesquiterpene with a unique
  structure, was first isolated from a Chinese
  plant, Artemisia annua in 1970. Since that time
  and then, A. annua is continually grown in
  several parts of the world to isolate artmisinin
  which was found to exhibit potent anti-malarial
  effect, beside weak cytotoxic and anti-microbial
  activity.

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• Activities of Artemisinin derivatives
• Anti-cancer
• Anti-malarial
• Anti-fungal

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• Anti-cancer compounds
• Around the world, an estimated 11 million new
  cancer cases occur annually. Cancer causes
  almost seven million deaths a year - a number
  that is on the increase.
• __________________________________________________
  _____________
• http// www.wcrf.org/research/cancer_facts

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• The high incidence of cancer is combined with
  serious adverse effects of conventional
  anti-cancer drugs.

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• This has shown the critical need for
  development of new anti-cancer agents, especially
  those with novel and selective mechanisms of
  action

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• The first artemisinin dimers to show strong
  anti-cancer activity were the symmetrical , and
  the unsymmetrical dimers. This finding was
  reported for the first time in 1993 by our group
  in collaboration with a group from
  Netherlands.1-3 --------------------------------
  ----------------------------- 1. J. Nat. Prod.
  1993, 56, 849. 2. J.Nat.Prod.1997, 60,325. 3.
  Planta Medica, 1998, 64, 615 1.

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• Recently, we have prepared a series of
  artemisinin-based acetal dimers and tested for
  anti-tumor activity in the National Cancer
  Institute (NCI) 60 cell lines assay. Additional
  testing of active compounds was carried out in
  the in-vivo Hollow Fiber Assay (HFA)1,2and
  studying the anti-angiogenic properties.
• -----------------------------------------------
• 1. U.S. Pat. Appl. Publ. (2004).
• 2. WO 2006/002105

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• These dimers were found to be active against
  solid tumors, with a pattern of selectivity that
  suggests a possible new mechanism of action.

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Key reactions in the synthesis of artemisinin
derivatives
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• Derivatives of artemisitene were cytotoxic in
  vitro to a number of human cell
  lines__________________________________
• Acta. Pharmacol. Sin 13 541-3 (1992)

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• Anti-cancer activity (GI50, µM)
• Cell Line 3 4 5 6 7
  8
• Leukemia
• MOLT-4 0.042 5.95 0.008 lt0.01 lt0.026 0.027
  
• Colon cancer
• COLO 205 0.049 5.64 0.011 lt0.01 0.006 0.011
  
• Prostate cancer
• PC-3 0.010 3.08 0.011 lt0.01 0.009 0.
  019
• Breast cancer
• MCF7 0.034 ------- 0.043 lt0.01 0.008 0.
  012

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• Anti-cancer activity (GI50, µM)
• Cell Line 9 10 11
  12 13 14
• Leukemia
• MOLT-4 0.298 0.02 0.1
  0.01 0.98 0.120
• Colon cancer
• Colo-205 0.040 0.007 lt0.01 0.01
  ------- 0.123
• Prostate cancer
• PC-3 0.035 0.010 lt0.01 lt0.01
  lt0.01 0.063
• Breast cancer
• MCF7 0.095 0.016
  0.042 lt0.010 lt0.010 0.148

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However, only the hemisuccinate and the oxime
dimers have been selected by the NCI for studies
further than the HFA, including toxicity,
absorption, blood concentration and other
parameters.
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High yielding method for preparation of the
ketone and the glycerol dimers
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• Anti-malarial compounds
• Malaria is responsible for 2-3 million deaths
  in the world each year. The world wide number of
  malaria patients is estimated at 300 to 500
  million. Approximately one third of the world's
  population lives in malaria-endemic areas,
  including Central and South America, Asia, and
  Africa.

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• Mosquitoes that carry malaria parasites have
  become resistant to insecticides, and the
  deadliest parasites have become resistant to
  previously effective antimalarial drugs such as
  chloroquine, quinine and other clinically used
  agents.

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• Because of the widespread incidence of malaria
  in certain parts of the world and the increasing
  parasite resistance to standard anti-malarial
  drugs, there is an urgent need for new
  anti-malarial drugs.

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• Interestingly, the anti-cancer artemisinin
  dimers exhibited anti-malarial activity, with
  some derivatives more active than artimisinin.

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• Anti-malarial activity (IC50, ng/mL)
  
• Comp. P. falciparum (D6 Clone) P. falciparum
  (W2 Clone)
• 2 6.5
  3.8
• 3 1.0
  0.74
• 4 8.5
  5.2
  
• 7 2.3
  3.1
  
• 8 11
  3.0
  
• Artemisinin 6-10
  6-10
• -------------------------------------------
• Chloroquine resistant strain

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• Anti-malarial activity (IC50, ng/mL
• Comp. P. falciparum (D6 Clone) P. falciparum
  (W2 Clone)
• 9 0.2
  0.74
• 12 0.7 0.2
• 10 3.0 5.2
• 11 3.5 8.6
• 13 1.0
  1.5
• 14 11 3.0
• Chloroquine 9.5 gt238
• Artemisinin 2.8 4.5
• --------------------------------------------------
  -----------------
• Chloroquine resistant strain

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• Anti-fungal compounds
• Incidence of fungal infections, in particular
  those associated with immunocompromised patients,
  has increased dramatically. Cryptococcuc
  neoformans is the cause of the most common
  life-threatening opportunistic fungal infections
  in patients with HIV/AIDS
• To a lesser extent Candida albicans

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• Cryptococcosis, caused by Cryptococcuc
  neoformans involves infection of the central
  nervous system, which is often manifested as
  meningitis, and is now seen most often in
  patients with AIDS, of whom 2-20 develop the
  condition.

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• In addition, candidiasis caused by Candida
  albicans is also one of the most frequent (though
  uncommonly life-threatening) fungal infections
  attacking persons with HIV/AIDS.

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• On the other hand, development of resistance,
  particularly with suppressed immunity, is a
  challenging problem in treatment of fungal
  infections

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• Antifungal artemisinin derivatives
• A series of artemisinin derivatives were
  prepared and tested for antifungal activity
  against two opportunistic pathogens, Candida
  albicans and Cryptoccocus neoformans.
• ..................................................
  ......
• J. Nat. Prod. 68, 1274, 2005
• .

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• Of all the compounds tested,
  anhydrodihydro-artemisinin (enol ether),
  demonstrated antifungal activity against C.
  neoformans, that was stronger than amphotericin
  B. Also, ?-arteether, and ?-arteether showed
  marked activity against C. neoformans. Against
  C. albicans, the overall antifungal effect of
  these compounds, was weak or negligible.

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Anticryptococcal activity (ACrA) and anticandidal
activity (ACA)
Amphotericin B (ASA)
IC50 / MIC (µg/mL) 0.35 / 0.625
Amphotericin B (ACA)
0.1 / .15
Artemisinin
Enol ether
0.045 / 0.195
IC50 / MIC (µg/mL) 2.0 / 50
ACrA
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• It was found that the anticandidal effect of
  these artemisinin derivatives was weak or
  negligible.

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Anticryptococcal activity
IC50 / MIC (µg/mL) 0.045 / 1.56
IC50 / MIC (µg/mL) 0.085 / 3.13
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IC50 / MIC (µg/mL) 0.078 /-
IC50 / MIC (µg/mL) 0.31 /-
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dihydroartemisinin
IC50 / MIC (µg/mL) 0.09 /12.5
IC50 / MIC (µg/mL) 0.045 /-
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IC50 / MIC (µg/mL) 0.45 / 12.5
IC50 / MIC (µg/mL) 4.5 /-
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IC50 / MIC (µg/mL) 1.0 / 25
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• Acknowledgments
• The authors thank the United States Department
  of Agriculture, the School of Pharmacy,
  University of Mississippi, and the National
  Cancer Institute, USA, for providing diverse and
  continual support during the whole study.

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• Special regards are due to the Research Center
  of the College of Pharmacy, King Saud University
  that made this presentation possible.

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• Thank you

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