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Microsoft word - a-1-8-rasoanaivo

11th NAPRECA Symposium Book of Proceedings, Antananarivo, Madagascar Natural Products and Drug Discovery through a Network of Partnerships
Philippe Rasoanaivo, David Ramanitrahasimbola, Dina Rakotondramanana, Voahangy Ramanandraibe, Suzanne Ratsimamanga Institut Malgache de Recherches Appliquées
Abstract
We present here relevant result obtained from a network of collaborations. Malaria
programme ranging from screening to investigation of mechanism of action has been
conducted in collaboration with the Muséum National d’Histoire Naturelle in Paris, the
Institut de Chimie des Substances Naturelles (CNRS), the Istituto Superiore di Sanità di
Roma
, the Università degli Studi di Roma “La Sapienza”, the Université de Montpellier II,
the Université des Sciences et Technologies de Lille, the University of Cape Town. The
cancer MDR modulator programme has been done at the University of Illinois at Chicago, in
collaboration with our Institute. The antiviral and anti-inflammatory programme has been
done in collaboration with the Università del Piemonte Orientale, and the University of
British Columbia in Vancouver.
Key words: Drug biodiscovery; partnerships; malaria; antiviral; anti-inflammatory; integrated

Introductory remarks

Although powerful new technologies such as high-throughput screening and combinatorial
chemistry are revolutionizing drug discovery, natural products still offer structural diversity
which makes them a valuable source of novel lead compounds, allowing the design and
rational planning of new drugs. In addition, some natural products to cite muscarine,
cannabinoids, forskolin, colchichine, are important tools used in pharmacological,
physiological and biochemical studies.
Basically, drug development involving natural products is a multi-disciplinary process. The
basic sciences involved are botany, ethnobotany, chemistry and pharmacology. Any research
into pharmacological active natural compounds depends on the integration of these sciences.
The way they are integrated and the extent of integration depend on the objective of the study.
For researchers in Africa, successful drug biodiscovery needs multi-centre partnerships with a
complementary expertise; otherwise the results may not be robust enough and may lead to
breakdown of the process. We report here relevant results through a network of partnerships.
Malaria programme

Background

Despite strong efforts to control it, malaria still remains a disease of importance afflicting
particularly the populations of developing countries, with an estimated 300 millions cases and
2 millions deaths each year, and the global morbidity and mortality have not significantly
changed over the past 50 years. One main reason for continued or, in some areas, rising rate
of malaria infection are attributable to the spread of drug-resistant strains of Plasmodium
11th NAPRECA Symposium Book of Proceedings, Antananarivo, Madagascar malaria, and the failure to get the existing, effective drugs to be applied in those areas where they can be of most benefit. During the 1985’s, malaria re-emerged in the central Highlands of Madagascar as the most devastating of the country’s tropical diseases. The severity of the infection is such that local populations now recognize the hitherto unknown condition to which they have given the name bemangovitra (disease of great shivering). Shortage of appropriate antimalarial drugs at that time led the populations, especially those living in the countryside, back to the massive use of traditional herbal remedies. Following this sudden recrudescence of malaria, our Institute started in 1988 a research programme, in collaboration with French and Italian laboratories, with the aim of evaluating the antiplasmodial activity of medicinal plants used to treat malaria. After seven years experience in ethnobotanical field work related to malaria, we came up with an integrated approach to antimalarial plants. We therefore expanded our screening programme to the evaluation of the cytotoxicity and the immunomodulating activities of plant extracts. And recently, we set up and implemented in vivo antiplasmodial screening in the liver stage of malaria parasites, while the in vitro tests are yet done at Immunobiologie Cellulaire et Moléculaire des Infections Parasitaires, Centre Hospitalier-Universitaire Pitié-Salpêtrière, Université Pierre et Marie Curie in Paris. This integrated approach can be summarized in the diagram below. Direct effect on parasite
ANTIMALARIAL PLANTS
Effect on host-parasite relationships
Chemosensitizers in malaria At the inception of our programme on malaria chemotherapy, we focused our studies on medicinal plants that could reverse chloroquine resistance in malaria. To this end, we learned from ethnobotanical field works conducted in the period 1987-1992 that rural populations in Madagascar treat bemangovitra by means of self-medication with 1-2 tablets of chloroquine (a dose thought to promote chloroquine resistance), together with a decoction made from various plant species termed chloroquine-adjuvants [1]. Among several plants investigated, 11th NAPRECA Symposium Book of Proceedings, Antananarivo, Madagascar Madagascan Strychnos species yielded two major bioactive constituents, malagashanine and strychnobrasiline [2].
Malagashanine turned out to be the parent compound of a new subtype of Strychnos alkaloids,
the C-21,Nb-secocuran indole alkaloids, isolated so far from Malagasy Strychnos. It had a
weak antiplasmodial action, but when combined to chloroquine at concentrations much lower
than required for antimalarial effect, it enhanced in vitro and in vivo chloroquine action
against chloroquine-resistant strains of Plasmodium malaria. Minor alkaloids structurally
related to the parent compound malagashanine were also isolated [3. 4]. This part of the work
was done in collaboration with the Muséum National d’Histoire Naturelle in Paris, the Institut
de Chimie des Substances Naturelles
, CNRS, the Istituto Superiore di Sanità in Roma, and
the Unversità degli Studi di Roma “La Sapienza”.
The hepatic stage of malaria parasite

The inaugural meeting of RITAM (Research Initiative on Traditional Antimalaria Methods)
held in Moshi (Tanzania) in December 1999 opened a new way to the Malaria Laboratory of
IMRA for the screening of extracts that may display antiplasmodial activities in the hepatic
stage of malaria parasites. To this end, few selected antimalarial plants that were previously
screened for antiplasmodial/chemosensitizing activities in the erythrocytic stage of malaria
parasites were screened against the Plasmodium liver stage. As a result, aqueous extract of
Strychnopsis thouarsii Baillon (Menispermaceae) exhibited significant in vitro and in vivo
activities against the hepatic Plasmodium schizonts. A new morphinan alkaloid named
tazopsine was found to be the active constituent [5, 6]. To he best of our knowledge, this is
the first report on natural products that are active in the hepatic stage of malaria parasites. All
the biological work was done at the INSERM U 511, Centre Hospitalier-Universitaire Pitié-
Salpêtrière, Université Pierre & Marie Curie
, Paris. This species was previously investigated
for intrinsic antiplasmodial effects and drug reversing activities, and a known bis-
benzylisoquinoline, fangchinolin, were shown to be the bioactive constituent [7].
11th NAPRECA Symposium Book of Proceedings, Antananarivo, Madagascar Semisynthesis

Going back to malaria chemosensitizers, it was useful to transform strychnobrasiline which
was inactive in vivo in drug combination into malagashanine derivatives. Thus, the oxidation
of strychnobrasline with meta-chloroperbenzoic acid led to an unexpected Bayer-Villiger
rearrangement [8]. Then the hemisynthesis of malagashanine derivatives using deacetyl-
strychnobrasiline as starting material was achieved in nine steps [9].
Based on the relevant results in which the introduction of a ferrocene into the side chain of
chloroquine has led to a very active derivative, a ferrocene derivative of strychnobrasiline,
was also prepared [10]. This was done in collaboration with the Université des Sciences et
Technologies de Lille
,
Chemosensitizing pharmacophore: hypothesis and synthesis

All naturally-occurring and hemisynthetic Strychnos alkaloids we isolated or prepared
reversed in vitro chloroquine resistance. Careful examination of these structures suggested
that the 1,4-diamino unit or N-phenyl-1,3-diamino propane of the tryptamine moieties might
be a basic structure requirement for chemosensitizing activity in malaria. Careful inspection
of the structures of synthetic chemosensitizers surprisingly showed that, although they appear
to possess unrelated structures, most of them have in common a basic fragment. As shown in
Figure 1, this fragment can be found embedded in the calcium entry blockers such as
verapamil, in some tricyclic antidepressants to cite desipramine, amitriptyline, and in some
tricyclic antihistaminics to name cyproheptadine, chloropromazine and penfluridol.
Fig. 1: Postulated reversing pharmacophore (in bold) 11th NAPRECA Symposium Book of Proceedings, Antananarivo, Madagascar This led us to postulate the unifying structure requirement for reversal activity -S-(C)n-S’, in
which S and S’ = aromatic group or nitrogen and n = 3, 4, 5, 6. Synthesis of derivatives was
achieved, and pharmacological testings confirmed our assumption [11]. This part of the work
was done in collaboration with the Department of Chemistry of the University of Cape Town.

The 1,4-diamino structure is reminiscent of that of polyamines, namely putrescine, and by
extrapolation spermidine and spermine which play a central role in cellular growth,
differentiation and neoplastic transformation. Accordingly, polyamine-based structures may
offer a wide range of structural possibilities, basically by substituting some of the nitrogen
atoms by phenyl groups, in designing new antimalarial drugs or chemosensitizers with useful
clinical relevance in the treatment of malaria and other parasitic diseases. In this regard, our
on-going synthesis work done in collaboration with the Université des Sciences et
technologies de Lille
within the frame of PhD training has generated bioactive compounds
and may yield promising leads [12].

Malagashanine as biochemical tool
Surprisingly, chloroquine has both a 1,4-diamino fragment in its structure. Is it coincidence
with our proposed pharmacophore or whether the data are relevant in understanding
chloroquine resistance? We have used malagashanine as a biochemical tool to probe the
mechanism of chloroquine resistance and its reversal. At this point, we came up with a
hypothesis in which we postulated for the first time the existence of a bi-directional,
reversible chloroquine transporter [13]. Reversing chloroquine resistance would consist in
restoring the initial chloroquine importer function of this transporter. This work was done in
collaboration with the Université of Montpellier.
MDR in cancer and chemosensitizers

Within the frame of the official collaboration with the Institut Malgache de Recherches
Appliquées
and the College of Pharmacy of the University of Illinois at Chicago, several plant
extracts were screened in 1992-1995 for anticancer/chemosentizing activities. One prominent
result arose from this collaborative work. In effect, several new tropane alkaloid aromatic
esters named pervilleines A-F were isolated from Erythroxylum pervillei Baillon
(Erythroxylaceae). They were found to be excellent modulators of the MDR phenotype, with
magnitude comparable to the standard MDR modulators verapamil and cyclosporine [14].
These compounds are being further investigated within the Rapid Access to Invention
Development (RAID) Programme of the US National Cancer Institute.
Other new tropane ester alkaloids were isolated from a large re-collection of the species as
minor constituents [15].
11th NAPRECA Symposium Book of Proceedings, Antananarivo, Madagascar Fig. 2: Similarities between verapamil structure and a chemosensitizing pharmacophore (in bold) identified from a pervilleine structure
In carefully dissecting the structure of the reference compound verapamil and those of
pervilleine series (Fig. 2), it is easy to extract a verapamil-like pharmacophore, which further
supports our unifying chemosensitizing pharmacophore.
Anti-inflammatory - antiviral pathway

We learned from a Colleague at the Università del Piemonte Orientale, Milano, that Italian
Helichrysum species hold phloroglucinol derivatives with good antiparasitic and anti-
infectious activities. Based on this information, we selected relevant Madagascan
Helichrysum for biological screening within a collaborative research. H. cordifolium was
found to have strong and selective antiviral activities, and also inhibited NFκB [16].
Independently, following a long-standing contact with the University of British Columbia in
Vancouver, we learned that Baobab had strong antiviral activities [17]. We then tested leaves
of Adansonia madagascariensis within this programme, and found that it displayed very
potent antiviral activities and also anti-inflammatory potency by measuring several different
cytokines. We therefore came up with an integrated approach outlined below to screen
medicinal plants used to treat vascular and pulmonary disorders, using isolated-based
techniques available in our Institute.
11th NAPRECA Symposium Book of Proceedings, Antananarivo, Madagascar Within the frame of vaso-/bronxcho-relaxing plant programme, we investigated Phymatodes
scolopendria
used to treat asthma in the east region of Madagascar, and found coumarin to be
the active constituent [18].
Conclusion

The combinatorial chemistry is now making very large numbers of compounds of pre-selected
structural types available for screening. It is hard to compete with such a potential for
discovery. Despite this, natural products remain an untapped source of leads whose structures
may challenge the imagination of medicinal chemists. In our opinion, one area of importance
for Africa is the discovery of new drugs for the treatment of parasitic diseases. They are the
biggest and most paralyzing health problem of African countries. We believe that modern
natural products research has a chance to discover such drugs. Referring to malaria, quinine
was discovered from the South-American biodiversity, and artemisinin from the Asian
biodiversity. It is hoped that the next powerful naturally-occurring antimalarial will come
from African biodiversity.
Acknowledgments

Financial support from Agence Universitaire de la Francophonie, Programme PAL+ of the
French Ministry of Education and Research, the International Development Research Centre,
and the International Foundation for Science, is gratefully acknowledged.
References

1. P. Rasoanaivo, A. Petitjean, S. Ratsimamanga-Urverg, A. Rakoto-Ratsimamanga (1992)
Medicinal plants used to treat malaria in Madagascar, J. Ethnopharmacol., 37, 117-127. 2. P. Rasoanaivo, S. Ratsimamanga-Urverg, R. Milijaona, H. Rafatro, C. Galeffi, M. Nicoletti (1994) In vitro and in vivo chloroquine potentiating action of Strychnos myrtoides alkaloids against chloroquine-resistant strain of Plasmodium malaria, Planta Med., 60, 13-16. 3. M.-T. Martin P. Rasoanaivo, G. Palazzino, C. Galeffi, M. Nicoletti, F. Trigalo, F. Frappier (1999) Minor Nb-(C21) secocuran alkaloids of Strychnos myrtoides, Phytochemistry, 51, 479-486. 4. P. Rasoanaivo, G. Palazzino, C. Galeffi, M. Nicoletti (2001) The co-occurrence of C(3) epimer Nb,C(21)-secocuran alkaloids in Strychnos diplotricha and S. myrtoides, Phytochemistry, 56/8, 863-867. 5. rM. Carraz, F. Frappier, P. Rasoanaivo, D. Mazier, A. Jossang, (2005) Tazopsine, a novel morphinan for malaria prophylaxis. First application of BPG for assignment of absolute configuration of secondary amine, Phytochemistry (submitted). 6. M. Carraz, A. Jossang, J.-F. Franetich, A. Siau, L. Ciceron, L. Hannoun, R. Sauerwein, F. Frappier, P. Rasoanaivo, G. Snounou, D. Mazier (2005) A plant-derived morphinan as a novel lead compound active against malaria liver stages, Nature Medicine (submitted). 7. S. Ratsimamanga-Urverg, P. Rasoanaivo, L. Ramiaramanana, R. Milijaona, H. Rafatro, F. Verdier, J. Le Bras, A. Rakoto-Ratsimamanga (1992) In vitro antimalarial activity and chloroquine potentiating action of BBIQ enantiomers from Strychnopsis thouarsii and Spirospermum penduliflorum, Planta Med., 58, 540-543. 8. F. Trigalo, M. T. Martin, A. Blond, B. Rasolondratovo, P. Rasoanaivo, F. Frappier (2002) Oxydation of indolines to nitrones and new rearrangements in seco-curane type indole alkaloids, Tetrahedron, 58, 4555-58. 11th NAPRECA Symposium Book of Proceedings, Antananarivo, Madagascar 9. F. Trigalo, R. Joyeau, V. C. Pham, J. J. Youté, P. Rasoanaivo, F. Frappier (2004) Synthesis of modulators of chloroquine resistance in Plasmodium falciparum, analogues of malagashanine from strychnobrasiline, Tetrahedron, 60, 5471-5474. 10. D. Razafimahefa, L. Pélinski, M.-T. Martin, D. Ramanitrahasimbola, P. Rasoanaivo, J. Brocard (2005). Synthesis and chloroquine-enhancing activity of N-deacetyl-ferrocenoyl-strychnobrasiline, Bioorg. Med. Chem. Let., 15, 1239-1241. 11. F. Chouteau, D. Ramanitrahasimbola, P. Rasoanaivo, K. Chibale (2005) Exploiting a basic chemosensitizing pharmacophore hypothesis. Part 1: design, synthesis and biological evaluation of novel bicyclic chemosensitizers against drug-resistant malaria parasites, Bioorg. Med. Chem. Let., 15, 3024-3028. 12. O. L. Rakotonnandrasana (2004). Synthèse et activités chimioréversantes de diamines, Mémoire DEA, Ecole Supérieure Polytechnique d’Antananarivo. 13. D. Ramanitrahasimbola, P. Rasoanaivo, S. Ratsimamanga, H. Vial (2005) Malagashanine potentiates chloroquine antimalarial activity in chloroquine resistant Plasmodium strains by modifying both its efflux and influx. Mol. Biochem. Parasitol. (in press) 14. B. Cui, G. L. Silva, D. Chavez, M. You, H.-B. Chai, P. Rasoanaivo, S. M. Lynn, M. O’Neill, J. A. Lewis, J. M. Besterman, A. Monks, N. R. Farnsworth, G. A. Cordell, J. M. Pezzuto, A. D. Kinghorn (2001) Modulation of the multidrug-resistance phenotypes by new tropane alkaloid aromatic esters from Erythroxylum pervillei, J. Nat. Prod., 64, 1514-1520. 15. Y.-W. Chin, W. P. Jones, T. J. Waybright, T. G. McCloud, P. Rasoanaivo, G. M. Cragg, J. M. Cassady, A. D. Kinghorn (2006) Tropane aromatic ester alkaloids obtained from a large-scale recollection of Erythroxylum pervillei stem bark collected in Madagascar, J. Nat. Prod. (in press). 16. B. Andriamihaja, B. Razanamahefa Bakonirina, D. Razafimahefa, P. Ratalata, P. Rabeson, P. Rasoanaivo, G. Appendino, H. Ranarivelo, F. Almeda, F. Van Berkum, K. Parker, P. Wright, Ojima Iwao (2005) Découverte de médicaments et Conservation de la biodiversité à Madagascar, 11th NAPRECA Symposium, August 2005, Antananarivo, Madagascar. 17. J. B. Hudson, M. K. Lee, P. Rasoanaivo (2000) Antiviral activities in plants endemic to Madagascar, Pharm. Biol., 38, 36-39. 18. D. Ramanitrahasimbola, D. L. Rakotondramanana, P. Rasoanaivo, A. Randriantsoa, G. Palazzino, C. Galeffi, M. Nicoletti (2005). Bronchodilator activity of Phymatodes scolopendria and its bioactive constituent, J. Ethnopharmacol., 102, 400-407.

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