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Research group coordinate by Prof. Anna Sparatore  

Group leader: Prof. ANNA SPARATORE

Ph.D Student:  Dott. ssa Anna Barteselli

1) Design and synthesis of new H2S-donating hybrids and study of their therapeutic potential in different pathologies.
This novel approach used in Prof.Sparatore’s lab to synthesize new drugs arises from the recent discovery of the physiological role of hydrogen sulphide (H2S). In particular this gaseous mediator affects the cellular inflammatory activation, by interacting at several intracellular signalling levels, such as  signals, genes, mediators through transcription factor regulation and Reactive Oxygen Species (ROS) neutralization. Furthermore, cytoprotective properties, also via GSH production on several tissues,  have been recently reported.
 This technology consists in the chemical insertion of an H2S-donating moiety into established known drugs resulting in new chemical entities with significant improvement of activity and/or safety. In-vivo the new chemical entity releases the parent compound which acts according to its own characteristics, while the slowly released H2S has marked activity in inflammatory cells and cytoprotective effect in non inflamed tissue. Scientific evidence shows that H2S interacts on redox imbalance processes such as Reactive Oxygen Species (ROS) generation and Transcription Factor  (TF) activation. The new chemical entities have increased activity and/or safety affecting cell activation at different levels (signals, genes, mediators), such as ROS, NF-kB, COX, etc. Some examples of the results so far achieved in different fields are:
- Inflammation: ACS 15, an H2S-releasing diclofenac derivative, results to be more effective and potent than the conventional agent diclofenac in several inflammation models. The new agent is also better tolerated and spares target systems, such as gastrointestinal tract and cardiovascular system in animals.
Li L, Rossoni G, Sparatore A, Lee LC, Del Soldato P, Moore PK. Anti-inflammatory and gastrointestinal effects of a novel diclofenac derivative. Free Radic Biol Med. 2007;42:706-19.

- Cardiovascular: the aspirin derivative ACS 14 shows thromboxane inhibition comparable with the parent compound. Unlike aspirin, ACS 14  spares GI tract and affects  redox imbalance by increasing GSH. This compound could be useful for the treatment of  “metabolic syndrome”.
Sparatore A, Perrino E, Tazzari V, Giustarini D, Rossi R, Rossoni G, Erdmann K, Schröder H, Del Soldato P. Pharmacological profile of a novel H(2)S-releasing aspirin. Free Radic Biol Med. 2009;46:586-92.

- Urology: new PDE-5 inhibitors for the treatment of erectile dysfunction (ED), benign prostate hyperplasia (BPH) and lower urinary tract symptoms (LUTS) were prepared. The sildenaafil derivative ACS 6 increases cGMP, cAMP and GSH in prostate, bladder and corpus cavernosum. ACS 6 inhibits also prostate cell proliferation in a greater way than sildenafil at nM levels.

- Neurodegeneration: L-DOPA derivatives show significant antiinflammatory, antioxidant, neuroprotective and MAO-B inhibitory activities, besides increasing intracerebral dopamine concentration. All these features are particular useful in the treatment of Parkinson desease.
    In the ocular field: the latanoprost derivative ACS 67 increases anti-intraocular pressure response with a concomitant  marked increase in GSH aqueous humor levels more than latanoprost. Unlike latanoprost, ACS 67 possesses significant retinal protective effects.

In conclusion, the new hybrids show remarkable improvement in activity and tolerability  compared to the related parent compounds.

2) Design and synthesis of dithiolethione-derivatives for cancer prevention and treatment.
It is known that some natural or synthetic ditiolethiones are endowed with cancer chemopreventive properties. Novel dithiolethiones derivatives were synthesised with the aim to achieve new anticancer drugs  acting with a multitarget mechanism. Indeed, studies carried out in collaboration with NCI (USA) showed that some of the new compounds significantly inhibited in vitro and in vivo cells proliferation (NSCLC xenograft in nude mice), enhancing E-cadherin and the tumor suppressor PP2A. Moreover these compounds inhibited the activity and expression of several carcinogen activating enzymes as well as induced the expression of several carcinogen detoxification enzymes of the glutathione cycle.  These results indicate that these compounds may be beneficial in cancer chemoprevention and /or therapy of NSLC.
    In addition, recently Prof. Sparatore’s research group has demonstrated that some dithiolethiones and thiosulfonates compounds have histone deacetylase (HDAC) inhibitory activity and that coupling these moieties with valproic acid (VPA) lead to new VPA derivatives endowed with much stronger inhibitory properties and anticancer activities compared to the parent compound. On this basis, we are studying these sulfurated compounds as chemical scaffolds for preparing novel HDAC inhibitory agents through the usual SAR studies.

3) Design and synthesis of novel antimalarials.
This research project is related to the synthesis of molecules endowed with activity against chloroquine-resistant strains of Plasmodium falciparum through different mechanisms, especially during the intraerithrocytary growth phase of plasmodium. Many compounds designed as chloroquine, amodiaquine and tebuquine analogs have been already synthesized and patented. Among them, quinolizidine and pyrrolizidine derivatives resulted particularly interesting, with excellent in vitro (IC50 in nanomolar range) and in vivo activity in murine malaria models. Presently, efforts are focused on the research of new chemical scaffolds endowed with antimalarial activity and devoided of resistance.
Sparatore A, Basilico N, Casagrande M, Parapini S, Taramelli D, Brun R, Wittlin S, Sparatore F. Antimalarial activity of novel pyrrolizidinyl derivatives of 4-aminoquinoline. Bioorg Med Chem Lett. 2008;18:3737-40

National and International collaborations:
Kinsmen laboratory of Neurological Research, University of British Columbia-Vancouver  Canada. (P. McGeer)  
Nuffield Laboratory of Ophthalmology, University of Oxford, UK. (N.Osborne);
Dept. of Pharmacology, National University of Singapore, Singapore (J. Bian)
Dept. of Pharmaceutics, University of Minnesota, Minneapolis, USA. (H. Schröder)
Dept. of Cardiology,  Shanghai Ninth People's Hospital Affiliated to Shanghai JiaoTong   University School of Medicine, Shanghai. China (Z. Huili)
National Cancer Institute, Bethesda, USA; (D. Wink, D.D. Roberts, T.W. Moody)
Laboratory of Methabolism, NCI-Frederick, Frederick, MD, USA (G.C.Yeh)    
Swiss Tropical Institute, Basel, Switzerland (R. Brun, S. Wittlin)
Istituto Oncologico Romagnolo per lo Studio e la cura dei Tumori (IRST), Forlì (W. Zoli)
Laboratory of Pharmacology and Toxicology, Dept. of Evolutionary Biology. Univ. of Siena, Italy (R. Rossi).

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