Summary Research Topics

 
 
MEDICINAL CHEMISTRY IN NATURAL PRODUCTS
 
 
Since the beginnings of our studies about the natural products, (S)-(+)-Boldine (2,9-dihydroxy-1,10-dimethoxy-N-methyl-4H-dibenzo[de,g]quinoline) from boldo tree (Peumus boldus Molina. Monimiaceae), native to the central region of Chile, it has shown wide pharmacological activities unknown for many people. Thus, it has been characterized in the past few years as an antioxidant that effectively protects different systems against free-radical-induced lipid peroxidation or enzyme inactivation. This activity presumably underlies the hepatoprotective and cytoprotective effects recently demostrated fot this alkaloid and may also be related  to its antipyretic and antiinflammatory behaviour, and to its protective effect in experimental colitis. Independently of these properties, boldine is a slightly selective R1A-adrenergic antagonist in vascular tissue and a nonselective D1- and D2-dopaminergic antagonist in the central nervous system. 
 
 
Taking into account these references, when (S)-(+)-Boldine was brominated, chlorinated and iodinated by using molecular bromine in acetic acid or N-halosuccinimides in trifluoroacetic acid, there they were afforded 3-haloboldines- and 3,8-dihaloboldines. Radioligand binding studies of these products showed that halogenation of boldine at C-3 favors affinity for D1 (vs D2-) dopaminergic receptors, attaining a low nanomolar IC50 value in the case of 3-iodoboldine (http://pubs.acs.org/doi/abs/10.1021/np990433j). Furthermore, the versatility of the boldine in generating some compounds through electrophilic reactions, we are able to afford heterocycles on boldine between positions 8 and 9. Thus, oxazine- and oxazole- fused derivatives of the alkaloid boldine and their complete structural and spectral assignment by HMQC and HMBC experiments were carried out with promising pharmacological activities (http://onlinelibrary.wiley.com/doi/10.1002/mrc.852/abstract).
 
On the other hand, we are interested in studying new compounds with aporphine skeleton that to have wide pharmacological possibilities such as boldine. In this sense, a small group of isoquinoline alkaloids called "Oxoisoaporphine" (7H-dibenzo[de,h]quinolin-7-one) have been few study, whilst these compounds bearing different substitution patterns, can be isolated from Menispermum dauricum DC (Menispermaceae). Synthetic oxoisoaporphines were afforded through cyclization of 3-(b-dialkoxyarylethylamino)phthalides, also be called "Azabenzanthrone", in high yield to give 2,3-dihydrooxoisoaporphine, that were the starting material to obtain them by using Pd/C as oxidative agent. Thus, several 2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one and 7H-dibenzo[de,h]quinolin-7-ones were catalytically hydrogenated over PtO2 in acetic acid to afford 7-hydroxyquinoline and quinolone derivatives with either total or partial hydrogenated benzene rings (https://www.thieme-connect.com/ejournals/abstract/synlett/doi/10.1055/s-2003-41422).
 
Unexpectedly the photoreduction of 5,6-dimethoxy-, 5-methoxy- and 2,3-dihydro-7H-dibenzo[de,h]quinolin-7-one (A) by tertiary amines in oxygen-free solutions generates long-lived semi-reduced metastable photoproducts, (A-NH-), via a stepwise electron-proton-electron transfer mechanism with a limit quantum yield of about 0.1 at high TEA concentrations. These metastable photoproducts revert thermally to the initial oxoisoaporphine nearly quantitatively in the presence or absence of oxygen (http://www.rsc.org/publishing/journals/PP/article.asp?doi=b310696a).
 
 
Finally, due to the interest of these compounds in the scope of the pharmacology of the isoquinoline derivatives such as the oxidated isomers of the aporphine called "Oxoaporphine" (7H-dibenzo[de,g]quinolin-7-one), "in vitro" assays of human monoamine oxidase inhibition (h-MAO) with several oxoisoaporphines, it allowed us to find derivatives with high selectivity for the isoform A (h-MAO-A). This fact will allow us to synthesize drugs of this alkaloid with low cost and with a wide variety of substitution patterns to the treatment of pathologies of major depressive disorder (http://www.wipo.int/pctdb/en/wo.jsp?WO=2009034216).
 
 
Vincent van Gogh's 1890 painting On the Threshold of Eternity


The studies “in vivo” of
animal behavior in the scientific literature for the search of new antidepressants compounds are very diverse. If the compounds to be evaluated possess antidepressant activity in laboratory mice through locomotion studies, they will be made of sharp and chronic form, and with different administration ways. This is made to discard the possible interferences that could arise in the behavior test and to observe that the mice maintain their intact functions. Example of it is the following video carried out with mice and some oxoisoaporphine derivatives. The experiment was carried out by Miriam Cebey López.


ANIMAL BEHAVIOUR WITH OXOISOAPORPHINE DERIVATIVES



Recently our research about the oxoisoaporphines pharmacology, in collaboration with the IRD (Institut de Recherche pour le Développement, France), we can to obtain unusual and selective results in the treatment "in vitro" of the Malaria, a tropical disease caused by the plasmodium parasite, Plasmodium falciparum. Such results have been protected through a Spanish Patent P201000501, which will allow us to design new antiparasitary drugs based in natural products with minor secundary effects. Our efforts are now directed in the discovery of new drugs against the Leishmaniasis, disease caused by protozoan parasites that belong to the genus Leishmania, and is transmitted by the bite of certain species of sand fly (subfamily Phlebotominae). Preliminary assays with several 2,3-dihydro- and oxoisoaporphine derivatives have shown a low nanomolar IC50 value, which to confirm the affinity and selectivity of these oxoisoaporphine alkaloids as antiparasitary drugs.
 

Malaria: Deadliest parasite on earth


A)


    
   B)
 


Leishmaniasis disease summary


           C)      
      
A) Plasmodium falciparum attacks inside the human blood cell.
B) Malaria is naturally transmitted by the bite of a female Anopheles mosquito.
C)
The Leishmania parasite feeds directly on the vital organs from the inside-out.
 


 
SUPRAMOLECULAR CHEMISTRY IN CYCLODEXTRINS 
 
 
According to the our new investigation about the carrier of several drugs through Central Nervous System (CNS), cell of different organs like liver, lung, heart, etc. potentially useful in the treatment of cancer, viral diseases and tropican infections that affect an important population in countries of the third world as the Malaria, we must consider the primary purpose of drug delivery systems such as to deliver the necessary amount of drug to the targeted site for a certain period of time., both efficiently and precisely. The important of carrier systems that can be versatile and from natural source for their low cost, it had contributed to development and study of cyclodextrin (CD) systems composed by sugar units as glucose. Cyclodextrins are potential candidates for such a role, because of their ability to alter physical, chemical, and biological properties of guest molecules through the formation of inclusion complexes. The ab and g-CD are widely used natural cyclodextrins, consisting of six, seven and eight D-glucopyranose residues, respectively, linked by R-1,4 glycosidic bonds into a macrocycle. Each cyclodextrin has its own ability to form inclusion complexes with specific guest, an ability which depends on a proper fit of the guest molecule into the hydrophobic cyclodextrin cavity. The most common pharmaceutical application of cyclodextrins is to enhance the solubility, stability, and bioavailability of drug molecules. 
However, natural cyclodextrins have relatively low solubility, both in water and organic solvents, which thus limits their uses in pharmaceutical formulations. Recently, various kinds of cyclodextrin derivatives have been prepared, so as to extend the physico-chemical properties and the inclusion ability of natural cyclodextrins as novel drug carriers.

 
Our preliminary results with b-cyclodextrin with its derivatives (HP-b-CD, DIME-b-CD) with two different type of compounds from natural source as coumarins and naphtho-quinolinone have been studied, due to the important fact of that both are DNA-well known intercalators framework useful in the treatment of cancer, but a few variety of these compounds are used with CD. Thus, 3-phenyl-coumarin derivatives have been tested as potentially anti-Parkinson drugs, due to its selectivity in the nanomolar IC50 values range (http://www.sciencedirect.com/s). Such compounds have the chemical structure of resveratrol, known antioxidant, anti-inflammatory substance found in red wine. Further studies of resveratrol revealed that it helps prevent blood clots by keeping blood vessels open and pliable. However, the low solubility of the 3-phenyl-coumarin in aqueous medium, it would facilitate the carrier through blood brain barrier (BBB) by using cyclodextrin in the CNS. In this case, DIME-b-CD showed to be the better carrier system, whilst HP-b-CD would not have major difference with the previous one.
 
 
Naphtho-quinolinone derivatives bearing N,N-dimethylamino- and nitro groups at C-2 and   C-6 respectively, they were used as target drug due to the references as a strongest DNA binding of similar chemical skeleton. Nevertheless, being a highly liposoluble compound, the possibilities to cross the lipid bilayer with polar substituent either OH or NH2 in its chemical framework will be very low. By using different temperatures and CD-derivatives, it was possible to know the high encapsulation of this alkaloid, being able to propose this type of heterocycle and their complexes with CD derivatives to study the phototherapy dynamic (PDT), since oxoisoaporphine and 3-aza-oxoisoaporphine derivatives showed to be photosensitizing agents (causing tissue susceptibility to certain lights), which is applied on the skin for a few hours before his exposure to a specific light (Spanish Patent P200902010). The formation of singlet oxygen by UV-light from oxoisoaporphine and 3-aza-oxoisoaporphine derivatives linked with a CD previously modified, it could give a successful answer for the anticancer and bactericidal treatments with low concentrations of this alkaloid that easily, they could cross the lipid bilayer of these microorganisms and killing the DNA inside.  The first steps are focused to the ability of oxoisoaporphine and 3-aza-oxoisoaporphine derivatives onto cancer cells, and later as part of supramolecular skeleton either with CD or other carrier systems as liposomes.
In this sense, Liposomes are bilayered phospholipid vesicles that have been proposed as vehicles for the selective delivery of cytotoxic drugs into malignant cells. "In vitro" and "in vivo" experiments have indicated that the activity of a range of drugs or their active metabolites may be enhanced by encapsulation in liposomes, particularly when used against drug-resistant tumours. Moreover, liposomal entrapment certainly has a marked effect on the tissue distribution and rates of clearance of cytotoxic drugs, and also appears to reduce their toxicity in most cases.
 
 
The supramolecular chemical structure that we will propose is by using derivatized naphtho-quinolinone or coumarins that can link it to cyclodextrin previously modified. Since synthetic liposomes are carried out by means of DPPC, the cyclodextrin used to be linked to the lipid bilayer would be modified previously by a simple synthetic route at the position 6, affording a mono-derivative. This synthetic proposal, and the ability to afford strongest complex to deliver the drugs across the time, they are being carrier out at the moment.
 

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