Design, synthesis, and toxicology of bioactive molecules (BioMOL)

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Group Coordinator: Maria Teresa Duarte

 

BioMOL is focused on multiple intertwining aspects of the chemistry and toxicology of biologically active molecules, both
endogenous and xenobiotic. It encompasses current and prospective therapeutic drugs, natural products, foodstuffs and
environmental pollutants, as well as biocompatible materials. A host of multidisciplinary skills, and a long history of group crosstalk
toward problem solving, ensure that documented expertise in different areas of chemistry, from synthetic and analytical chemistry
to structural analysis, chemical thermodynamics, reaction mechanisms, chemical toxicology and biochemistry and cellular biology,
is used to benefit the whole team. The group has been actively involved in a host of state-of-the-art training programs for young
researchers.

The scientific activity of BioMOL has successfully covered:
A- Design, synthesis, and activity evaluation of drug-like organic and organometallic target structures with prospective therapeutic
properties
B- Unconventional and/or ecofriendly synthetic strategies for high value added molecules, useful as synthons or models for
bioactive compounds
C- Synthesis and evaluation of novel structurally elaborate bioactive compounds: BioMOFs, Biobuffers, and biomimetic or
bioinspired multinuclear metal complexes.
D- Development/validation of sensitive MS and NMR methodologies, using synthetic biomarker standards (metabolites, DNA and
protein adducts), to screen environmental and human samples for exposure risks to endogenous and xenobiotic compounds
E- Improved in vivo performance or extended shelf life of active pharmaceutical ingredients (APIs)
F- Use of Crystal Engineering tools to study amorphous and co-amorphous APIs
G- Use of ionic liquids in energetics-structure studies to assess, control and avoid API Polymorphism
H- Molecular cell modulation of redox-regulated biochemical pathways involved in response to environmental cue (e.g. radiation,
nutrients and xenobiotics) and endogenous signals.

IDENTIFICATION OF HYDROGEN PEROXIDE (H2O2) TARGETS
H2O2 regulation of gene expression and signalling pathways is important for cellular homeostasis. Disruption of this redox
regulation (oxidative stress) is involved in several diseases. Identification of molecular targets for H2O2 is fundamental toward a
therapeutic approach for H2O2-dependent diseases. We identified two such new targets, namely the transcription factor Opi1p
and the inositol transporter Itr1p, which regulate lipid metabolism during biological adaptation to H2O2 in yeast, a process that
may mediate resistance to antimicrobials. We also derived mathematical equations that lay the foundation of H2O2 signalling,
give new insights on its mechanisms, and help gain new information (e.g., target identification) from common redox signalling
experiments.


COVALENTLY MODIFIED HISTONES AS COMPOUND-SPECIFIC BIOMARKERS OF CANCER
We obtained the first unequivocal evidence for the occurrence of histones covalently modified by electrophile-generating
chemicals (e.g., furan) in vivo, suggesting that these modifications may be general in scope. This observation opens new avenues
for the development of new compound-specific biomarkers of exposure and also for additional insights into the molecular
mechanisms of chemical toxicity and carcinogenesis. In particular, this discovery provides a plausible molecular basis for multiple
reports of aberrant epigenetic status and subsequent downstream changes in gene expression associated with exposure to
chemical carcinogens. Furthermore, we demonstrated that histone modification occurs at early stages of exposure, prior to the
identification of epigenetic changes, suggesting that the covalent modification of histones by chemical carcinogens or their
metabolic electrophiles may provide relevant early compound-specific biomarkers of cancer. This is anticipated to be useful for
accurate risk assessments, allowing efficient regulatory measures and ultimately leading to decreased incidence of chemicallyinduced
cancers.


NEW ANTIBACTERIAL AND ANTIMICROBIAL DRUGS
The increasing resistance of bacteria and fungi to the clinically available drugs is a threat to human life, fostering the urgent need
for new compounds that may become effective alternatives to the current antimicrobials. We developed bio-inspired metal
complexes and metal-organic frameworks (bioMOFs) to tackle this issue and explore different approaches, i.e.: i) designing new
aqua-soluble carboxylate-driven silver and copper bioMOFs with potent antibacterial and antifungal activity and possible
applications in topical antimicrobial formulations; (ii) synthesizing and optimizing the antimicrobial and/or cytotoxic activity of silver
and gold complexes through redesign of camphor ligands; (iii) promoting the direct coordination of antibiotics to metal centers,
forming complexes and MOFs with enhanced solubility, bioavailability and more efficient bactericidal properties.

 

Group photo

 

SELECTED PUBLICATIONS

1. André, V.; Braga, D.; Grepioni, F.; Duarte, M.T. (2009) Crystal forms of the antibiotic 4-aminosalicylic acid: solvates and molecular salts with dioxane, morpholine and piperazine; Crystal Growth & Design, 9, 5108-51116. DOI: 10.1021/cg900495s

2. Ferreira, A.P.; Ferreira da Silva, J.L.; Duarte, M.T.; Piedade, M.F.M.; Robalo, M.P.; Harjivan, S.G.; Marzano, C.; Gandin, V.; Marques, M.M. (2009) Synthesis and characterization of new organometallic benzo[b]thiophene derivatives with potential antitumor properties; Organometallics, 28, 5412-5423. DOI: 10.1021/om9003835

3. Pereira, L.; Coelho, A.V.; Viegas, C.A.; Ganachaud, C.; Lacazio, G.; Tron, T.; Robalo, M.P.; Martins, L.O.M. (2009) On the mechanism of biotransformation of the anthraquinonic dye Acid Blue 62 by laccases; Adv. Synth. Cat., 351, 1857-1865. DOI: 10.1002/adsc.200900271

4. Antunes, A.M.M.; Godinho, A.L.A.; Martins, I.L.; Oliveira, M.C.; Gomes, R.A.; Coelho, A.V.; Beland, F.A.; Marques,M.M. (2010) Protein adducts as prospective biomarkers of nevirapine toxicity; Chem. Res. Toxicol., 23, 1714-1725. DOI: 10.1021/tx100186t

5. André, V., Hardeman, A., Halasz, I., Stein, R.S., Jackson, G.J., Reid, D.G., Duer, M. J., Curfs, C., Duarte, M.T., Frišcic, T. (2011) Mechanosynthesis of the metallodrug bismuth subsalicylate from Bi2O3 and the first structural characterisation of a bismuth salicylate; Angew. Chem.-Int. Edit., 50, 7858-7861. DOI: 10.1002/anie.201103171

6. Lourenço, A.B.; Ascenso, J.R.; Sá-Correia, I. (2011) Metabolic insights into the yeast response to propionic acid based on high resolution 1H NMR spectroscopy; Metabolomics, 7, 457-468, 2011. DOI 10.1007/s11306-010-0264-1

7. Picchiochi; R.; Diogo, H.P.; Minas da Piedade, M.E. (2011) Thermodynamic characterization of three polymorphic forms of piracetam; J. Pharm. Sci., 100, 594-603. DOI: 10.1002/jps.22294

8. Caixas, U.; Antunes, A.M.M.; Marinho, A.T.; Godinho, A.L.A.; Grilo, N.M.; Marques, M.M., Oliveira, M.C.; Branco, T.; Monteiro, E.C.; Pereira, S.A. (2012) Evidence for nevirapine bioactivation in man: searching for the first step in the mechanism of nevirapine toxicity; Toxicology, 301, 33-39. DOI: 10.1016/j.tox.2012.06.013

9. Charneira, C.; Grilo, N.M.; Pereira S.A.,; Godinho, A.L.A.; Monteiro, E.C.; Marques, M.M.; Antunes, A.M.M. (2012) N-terminal valine adduct from the anti-HIV drug abacavir in rat hemoglobin as evidence for abacavir metabolism to a reactive aldehyde in vivo; Br. J. Pharmacol., 167, 1353-1361. DOI: 10.1111/j.1476-5381.2012.02079.x

10. Wanke, R.; Novais, D.A.; Harjivan, S.G; Marques, M.M.; Antunes, A.M.M. (2012) Biomimetic oxidation of aromatic xenobiotics: synthesis of the phenolic metabolites from the anti-HIV drug Efavirenz, Org. Biomol. Chem., 10, 4554-4561. DOI: 10.1039/c2ob25212k. HOT ARTICLE.