| Summary: |
The need for a continued search for new anti-infective and anticancer drugs is universally considered of great importance since
many of the current drugs are insufficiently effective, highly toxic, and resistances may be developed.
Our group has isolated two alkaloids, eurochevalierine, a potent inhibitor of the growth of human tumor cell lines [1], from the
soil fungus Neosartorya pseudofischeri, and neofiscalin A from the soil and marine fungus N. siamensis with potent
antibacterial activity [2]. Neofiscalin A exhibited also antibiofilm activity in both reference and multidrugs-resistant isolates,
and is currently in the patent filing process. On the other hands, marine fungi derived xanthones, particularly yicathins and
isomers were considered promising as chemotherapic agents [3]. So, eurochevalierine, neofiscalin A and yicathins can be
considered very interesting models to discover new anti-infective and anticancer drugs to overcome drug-resistance that could
represent innovative drug candidates. However, their availability to proceed to further investigations and their complex
structures could limit their future as drug candidates. Our group has multi- and transdisciplinary skills, with a large experience
in isolation and structure elucidation of natural products, synthesis, cellular and molecular biology and nanotechnology.
Moreover, the synthesis of anti-infective [4,5] and antitumor [6-10] xanthone derivatives, particularly in multidrugs-resistant
models [5,10], is the strength of our group. Therefore, this expertise can drive these natural products and derivatives with
enough potency and selectivity to become new potential anti-infective/antitumor clinical candidates.
However, our goal is not only to continue with the search for innovative marine-derived compounds but also to obtain
derivatives/formulations of the most promising compounds to obtain more efficient analogues. To achieve these goals, five
approaches will be undertaken: i) i  |
Summary
The need for a continued search for new anti-infective and anticancer drugs is universally considered of great importance since
many of the current drugs are insufficiently effective, highly toxic, and resistances may be developed.
Our group has isolated two alkaloids, eurochevalierine, a potent inhibitor of the growth of human tumor cell lines [1], from the
soil fungus Neosartorya pseudofischeri, and neofiscalin A from the soil and marine fungus N. siamensis with potent
antibacterial activity [2]. Neofiscalin A exhibited also antibiofilm activity in both reference and multidrugs-resistant isolates,
and is currently in the patent filing process. On the other hands, marine fungi derived xanthones, particularly yicathins and
isomers were considered promising as chemotherapic agents [3]. So, eurochevalierine, neofiscalin A and yicathins can be
considered very interesting models to discover new anti-infective and anticancer drugs to overcome drug-resistance that could
represent innovative drug candidates. However, their availability to proceed to further investigations and their complex
structures could limit their future as drug candidates. Our group has multi- and transdisciplinary skills, with a large experience
in isolation and structure elucidation of natural products, synthesis, cellular and molecular biology and nanotechnology.
Moreover, the synthesis of anti-infective [4,5] and antitumor [6-10] xanthone derivatives, particularly in multidrugs-resistant
models [5,10], is the strength of our group. Therefore, this expertise can drive these natural products and derivatives with
enough potency and selectivity to become new potential anti-infective/antitumor clinical candidates.
However, our goal is not only to continue with the search for innovative marine-derived compounds but also to obtain
derivatives/formulations of the most promising compounds to obtain more efficient analogues. To achieve these goals, five
approaches will be undertaken: i) isolate other bioactive compounds from the marine-derived N. pseudofischeri and N.
siamensis and other related strains; ii) synthesize eurochevalierine, neofiscalin A and yicathins to obtain more quantity of
these products for in vitro and in vivo tests, iii) carry out successive molecular modifications in order to achieve more efficient
analogues, iv) investigate their potential as anti-infective agents, v) perform in vitro studies in tumor cell lines; vi) incorporate
in nanoparticles in order to improve permeability and selectivity of the most promising compounds.
To carry out approach i) isolation of the bioactive metabolites, we will culture the fungi N. pseudofischeri and N. siamensis,
isolated from the marine environment, such as sponge or coral to obtain eurochevalierine, neofiscalin A, and structurally
related alkaloids. Moreover, we will also perform a co-culture of these two fungi with marine bacteria for the purpose of
increasing the quantity of the alkaloids eurochevalierine and neofiscalin A as well as to verify if the fungi also accumulate other
bioactive metabolites when compared to the pure cultures.
To carry out approaches ii)-iii) these alcaloids and yicathins will be synthesized and the (semi)synthesized derivatives will be
used to obtain a library of structurally-related analogues with improved efficacy. These results will allow us to establish
structure activity relationships (SAR), to contribute to define the important molecular features of anti-infective and antitumor
activities, and consequently, the design of more potent molecules.
To carry out approach iv), the new co |