On the scientific life of Francesco Pietra

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The above picture illustrates the structure of the acid-sensing ion channel cASIC1a, which is involved in ischaemic neuronal injury (F. Pietra, Chemistry&Biodiversity, 2015, 12, 350-357). What I carried out was the elucidation, as alpha helices, of the initial (highlighted in red) and final parts of the protein chain (highlighted in green). It is hoped that inhibition of ASIC channels, such as by Tarantula toxins, might relieve from pain upstream of opiate systems, thus avoiding the use of opium drugs.

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Liveliest in my memory is the High School, where I learned how to set a scientific project from the Latin scholar Vincenzo Courier, how to treat it from the mathematician Emilio Ceccarelli, and how to run a scientific institution from the Dean, the German scholar Achille Radaelli. It was Emilio Ceccarelli who stimulated me to complete the 4th and 5th years in one year only, and thereafter that become a close friendship.

 At the university, it were only the lectures in physical chemistry and electrochemistry by Antonio Foffani that left an indelible mark with me. Otherwise, that was a dull period. My interest in chemistry resurrected under the guidance by Antonino Fava as to the mechanisms of organic reactions, built on the mathematics that I had received from Emilio Ceccarelli. But the breakthrough was the 1965 textbook "Basic Principles of Organic Chemistry" by J.D.Roberts and  M.C. Caserio, which opened my mind to a combined classical and post-modern view of organic chemistry founded on thermodynamics. That, I must say, could be built on the thermodynamics that I had received from Antonio Foffani, and since then I never renounced to first examine all problems from the thermodynamic point of view. de Broglie's unifying view action/h=entropy/kB was my phylosophers' stone..  

This was my way toward the Libero Docenza in Chimica Organica Superiore, a kind of Italian PhD title, perhaps more extensive than that. For that I had received written support by J.F. Bunnet, the founder of Account of Chemical Research, with "On the basis of Dr. Pietra's research contributions, I would consider him well qualified  for appointment as associate professor (with tenure) in the University of California". Which resonated into the statement by the Italian committee, "Tutta la produzione scientifica del Pietra e' impostata e condotta con grande rigore scientiifico. I risultati da lui ottenuti  hanno avuto una notevole risonanza internazionale, come dimostrano inoltre le numerose citazioni di essi in qualificati libri e rassegne internazionali".

Shortly after those great days, on the stimulation by colleagues in Pisa, I applied for the position of professor of Physical Organic Chemistry. I got a phone call by Antonio Foffani, to my surprise member of the examination committee, to meet him in Bologna at his office. Things were running, the Faculty in Pisa was already organizing for my new position, but my application did not go on. That would have made my life easier, both in my family and with the many students carrying out their thesis work in my lab. I had to leave all them to earn my bread elsewhere instead of continuing with studies in physical organic chemistry.

t was not the sunset, however, as my association to to the group of Derek Barton at the Imperial College in London opened my eyes to the big organic chemistry. No telephone in Barton's office, every meeting was a concentration of attention and ideas, in the lovely atmosphere of South Kensington and the nearby Chelsea, where I had rented a small flat with my wife and my little daughter.The tennis court was 5p, squash was 5p, everything at the college was 5p.

My work continued with publications on Chemical Communications and other journals of the Royal Chemical Society, as well as on the top journal of the ACS, such as by G. Biggi, F. Del Cima and F. Pietra "Nucleophilic substitution with rearrangement on troponoids. The reaction of 2-(1-azoniabicyclo[2,2,2] oct-1-y1[3,5,7-2H3])cyclohepta-2,4,6-trien-1-one iodide with piperidine leading to 2-piperidino[4,6-2H2]cyclohepta-2,4,6-trien-1-one via 7,2 addition-elimination." Journal of the American Chemical Society, 1972, 94, 4700-4707.

This was the activity for a call as Invited Lecturer of the British Council for the year 1974 throughout Scotland and northern England.

 With the Chair of Organic Chemistry at the University of Trento, I was given all great means to start research on marine natural products. This included the search for novel marine natural products as well as organic synthesis devised to elucidate their structures and behavior. It was a very productive period, in a team of research assistants gathered from the universities of Naples, Bologna (Ciamician) and Padua and skilled technicians. This work was more connected than before with daily life, and brought me to close relationships with the research pharma. To secure samples of marine invertebrates and algae, I turned my leisure activity as a diver into professional activity by marine stations throughout the world, including the Stazione Zoologica di Ganzirri, the Station Zoologique de Villefranche, the INSERM 303 Villefranche-sur-Mer, the Station Marine d'Endoume a Marseille, the Laboratoire Arago a Banyuls-sur-Mer, the Station Biologique de Roscoff,  the Station Biologique Archachonne, the Hawaii Institute of Marine Biology at Coconut Island, the ORSTOM Centre de Noumea Nouvelle Caledonie, where I conceived what was a breakthrough in the thinking about natural products, unifying concepts about marine and terrestrial natural products, F. Pietra "Structurally similar natural products in phylogenetically distant marine organisms, and a comparison with terrestrial species" Chemical Society Reviews 1995, 24, 65-71.

In the year 1998 I was appointed to the Centro Linceo Beniamino Segre, at the Accademia Nazionale dei Lincei, Rome, and in the same year I was awarded the Maria Teresa Messori Roncaglia ed Eugenio Mari Chemistry Prize by the Accademia Nazionale dei Lincei.  

I delievered lectures at universities and other research centers. Those about which I had taken notice include ETH Zuerich (Prof Heinrich Zollinger) 1965 "Isotope effects in the nucleophilic reactions of protic amines with nitro-activated substrates". La Sapienza Universita' di Roma (Prof Gabriello Illuminati) 1965 "Meccanismi di reazioe di sostituzione nucleofila aromatica. Universita' di Bari (Prof E. Todesco) 1970 "Chimica di troponoidi". University of Dundee(Prof R. Foster) 1974. Strathclyde University Glasgow (Prof P.L. Pauson) 1974. Durham University (Dr M. Crampton) 1974. University of Liverpool (Prof C.W. Rees) 1974. UNESCO European Intensive Course, Banyuls-sur-Mer, August-September 1982. CNRS Gif-sur-Yvette (Professors Pierre Poitier and Derek Barton) 1985. IRD, Noumea 1995 "Capitalizing on natural product diversity of coral reefs".   Table Ronde sur la Caulerpa taxifolia, Carrefour Universitaire, Nice (Prof A. Meinesz) 1991. Seventh International Symposium on Marine Natural Products, Capri (Prof L. Minale) 1992.  La Sapienza Universita' Roma (Prof A. Ballio) 1992. Universita' di Camerino (Prof  ??) 1994. Marconi Symposium, Melbourne and Sydney,  as a representative of Italy for the Chemistry of Natural Products 1995. The University of Melbourne (Dr Robert Capon) 1995.  Pharmacia-Upjohn, Nerviano  1996. Antibioticos SpA, Milano 1996. Lepetit, Gerenzano, 1996. Boeringer Ingelheim Pharmaceuticals, Ridgebury Conn, 1998 "Chemistry in the chemistry of natural products. Universita' di Siena (Prof C. Rossi) 1998. Gordon Conference on Marine Natural Products, Ventura, Cal, 1998 "Secondary Metabolism and Genetics of Marine Free Living and Metazoan-Associated Microbes". Sigma Tau Pharmaceuticals, Pomezia 1999 "Diversita' molecolare dalla biodiversita' marina. 22nd IUPAC International Symposium on the Chemistry of Natural Products, Sao Carlos, Brazil, 2000 "Evolution of the secondary metabolite vs, evolution of the species". Perspectives of the Chemistry of Natural Organic Products, Istituto Lombardo Accademia di Scienze e Lettere, Milano 2002 "Stereochemistry and phylogeny". Accademia dei Lincei, Rome  1994 Symposium on Transition ???  "From the Phoenicians to modern genetic manipulations: the history of organic natural products"  year ?.

I acted as a referee for the appointment to chairs and the evaluation of PhD theses for Australia, France, New Caledonia and India. I also supported developing countries, in bringing to the Thèse d'État at the Université Cheikh Anta Diop, Dakar, a Senegalese student, Ibrahima N'Diaye (the son of a fisherman), following four years of research in my lab at the University of Trento. That at the Faculty in Dakar was a charming day for me, seeing the appreciation by the Dean and his colleagues for the contribution of my University of Trento for science in  Senegal, while perhaps three hundred blue-dressed beautiful girls were congratulating the new doctor in science. With my letter of support to the Center in Burkina Faso, Ibrahima was appointed Maître de Recherche at the Université Cheikh Anta Diop in Dakar.

I often think back to pieces of my work, enjoying the nostalgia for the coworkers of those days, Gino,   all my work .

 Following to be edited

 

Two lines of these studies are most relevant to human welfare. One concerns the sarcodictyins (M. D'Ambrosio, A. Guerriero, and F. Pietra "Sarcodictyin-A and sarcodictyin-B, novel diterpenoidic alcohols esterified by N(1)-methyl-(E)-urocanic acid. Isolation from the Mediterranean stolonifer Sarcodictyon roseum" Helvetica Chimica Acta, 1987, 70, 2019-2027), that led to the US Patent 5,869,514 with Pharmacia & Upjohn on these potent antitumor agents with Taxol-like activity, but also active on cancer lines that are resistant to Taxol. In view of recent experiments that show that Taxol acts by misregulating chromosome segregation, rather than by mitotic arrest, as was previously thought (B.A. Weaver, Sci Transl Med. 2014 March 26; 6(229): 229ra43. doi:10.1126/scitranslmed.3007965), it would be  interesting to carry out similar tests with the sarcodictyins. The problem is the availability. The stolonifer is relatively rare and culture of the entire coral or cells have never been attempted, as far as I know. On the other hand, the SCRIPPS total synthesis of sarcodictyin A ( J. Am. Chem. Soc., 1998, 120, 8661–8673) is too complex and of too low yield to be of industrial interest. Now, although Taxol needs to be replaced because it damages the long axons, efficient total synthesis of molecules that revealed Taxol-like activity, like the sarcodictyins, remains largely a dream. Too complex structures to be made in gram amounts. Actually, the scientific community, baffled from the difficulties, has largely abandoned the art of the total synthesis. Thus, the sarcodictyins are destined to remain as a golden piece in the literature rather than a weapon in the pharmacy against malignancies. However, the China makes the exception,  have taken massively the challenge of total synthesis. Total synthesis that appears in top scientific journals is now mainly made in China. Therefore, it is now my aim to stimulate Chinese to take the challenge of industrial-type total synthesis of the sarcodictyins by unraveling how the sarcodictyins are hosted by tubulin. I am now trying that computer simulations.

Other antitumor agents, that we isolated from a sponge of the south seas several years ago (the agelastatins  M. D'Ambrosio, A. Guerriero, C. Debitus, O. Ribes, J. Pusset,  S. Leroy, F Pietra "Agelastatin A, a new-skeleton cytotoxic alkaloid of the oroidin family. Isolation from the axinellid sponge Agelas dendromorpha of the Coral Sea" J. Chem. Soc., Chem. Commun., 1993, 1305-1306) are still of my interested. The bioactivity of the agelastatins has been recently patented by the Mayo Foundation for Medical Education and Research, Osaka University, against brain tumors (Treating brain cancer using agelastatin a (aa) and analogues thereof, PCT/US2013/064605, Apr 17, 2014). The agelastatins, although found in a relatively rare marine sponge, are amenable to industrial-type total synthesis, which paved the way to clinical trials.Interestingly, Michele D'Ambrosio (the only former coworker with whom I saved relationships) has visited me in July 17 at the Accademia,  stimulating me to continue with experimental chemistry of agelastatins.

 
 

 

During the Lincei period in Rome I was engaged in a major writing, F. Pietra “Biodiversity and Natural Product Diversity” (Tetrahedron Organic Chemistry Series, Volume 21); Elsevier, Oxford 2002. This book offers a new perspective on natural products, no more from only the chemical or biogenetic point of views, but also linking them to taxonomy and genetics as well.

 

I delivered named lectures at universities, symposiums, and the pharmaceutical industry throughout the world, including the Gordon Conferences. I represented Italy for the chemistry of biologically active natural products at the Marconi Symposium in Sydney and Melbourne in the year 1995. I also acted as a referee for the appointment to chairs and the evaluation of PhD theses for Australia, France, New Caledonia and India. In contrast, during my long career as a full professor, I was never asked to act as a referee for promotions at universities in my country.

 



 


 

 I retired from the university before the terms, disappointed by my failure to convince the Faculty in Trento to found a full degree in Biochemistry. Unique among developed (and most emerging) countries, the Italian university still does not offer such a fundamental degree. Then, I moved to theoretical studies, mainly on proteins and their interaction with the small molecule. An example is the unraveling of what was still hidden about the structure of the ASIC1a channel, as in the illustration at the top of this page.

 

Financial support to my research at the university came  from both public (MPI, CNR, EU European Projects) and private funding (Pharmacia&Upjohn, IRST), while the university itself provided rooms, water and electricity. Thereafter, during the Accademia Lucchese period, my research has been  financially supported by public funding (CINECA-ISCRA), to provide access to mainframes like the Blue-Gene and the IBM NextScale.

From my activity as a fiction writer:

F. Pietra “The old man and the roading dog” Gray's Sporting Journal (Augusta, Georgia, the leading sporting journal in the US) 2005, 30, 1316. It represents an insight into the psychology of the pointing dog and his prey.

 

A kind of paradise that did not last long, with the refusal by the Faculty to launch a full degree in Biochemistry, for which I had presented a plan patterned on Biochemistry at the Stanford University. Support by the Max Planck in  Rosenheim was not enough, I was left without students, while Trento and Italy lost a great opportunity. This is a story left to historians, with all original letters of support by scientists from all over the world, in an existing single copy at the library of the Accademia Lucchese under the tithe "The Short Life of the Institute of Chemistry at the University of Trento", 2008.