Collaboration With Prof. Michael Pollastri on Lead Diversification
HepatoChem Inc. and Prof. Michael Pollastri at Northeastern University initiated a collaboration on lead diversification of bioactive small molecules. The objective of this partnership is to discover new therapeutics using both the HepatoChem biomimetic technology and Pollastri’s approach, which consists of repurposing optimized human compound classes for neglected tropical diseases.
An example of Prof Pollastri’s approach is a parasitic target like trypanosomal phosphodiesterases has ~30% homology to human PDE4 and 5. That considered it becomes advantageous to use known human PDE4/5 inhibitors as a starting point to develop a new parasitic drug.
HepatoChem will bring its expertise in biomimetic technology to allow fast synthesis of new metabolite-like analogues. Indeed, the diversity expansion inherent in transformations that mimic the metabolism of small molecules and natural products provides a new direction into new chemical space. This new application is the result of the expansion of the spectrum of chemical reactions offered by HepatoChem to include halogenation and amination, in addition to oxidation.
This collaboration is part of the HepatoChem effort to develop and offer innovative tools for drug discovery. For more information about Prof Pollastri http://www.northeastern.edu/pollastri/
HepatoChem is a Recipient of the ‘Mass Life Science Center Life Science Center’s Accelerator Program
Mass Life Science Center Life Sciences Accelerator Program – Announces the 5 FY2012 Recipients on April 24, 2012
We are delighted to learn on April 24th that HepatoChem was one of five early stage companies to be awarded the Massachusetts Life Science Center Accelerator Program Loan for FY2012. “The $330,000.00 loan has arrived at the right time. Each month, small to big pharmaceutical organizations are turning to us to help them produce and characterize their drug candidate metabolites faster and in larger quantities than they could trying more traditional methods. To learn more …
Cationic Iron(III) Porphyrin-Catalyzed [4 + 2] Cycloaddition of Unactivated Aldehydes with Simple Dienes
Usually iron porphyrin complexes are studies as models of heme proteins and as biomimetic oxidation catalysts. Interestingly, simple iron porphyrins can also catalyze other important transformations of organic compounds. The team of Kyohei Fujiwara, Takuya Kurahashi, and Seijiro Matsubara at Kyoto University have reported that the readily available cationic tetraphenyl iron(III) porphyrin (FeTPP) is an efficient catalyst for the highly chemoselective hetero-Diels−Alder reaction of aldehydes with conjugated dienes.
This reaction is one of the most powerful synthetic methods for the construction of heterocyclic compounds containing the pyran structural motif and has been widely applied in the preparation of drugs and natural products. Significantly, the process did not require activated reaction partners. A crystal structure of the catalyst shows that aryl aldehydes are activated by the catalyst via coordination of the carbonyl oxygen to the iron(III) center. High functional group tolerance was observed and a large variety of cycloadduct products were obtained in good to excellent yield. For example, phenyl-acetaldehyde underwent cycloaddition to afford a pyran in 72% yield. Thus, the catalyst is apparently able to suppress the high tendancy of this substrate to enolize. Cyclopropane carboxaldehyde, which is sensitive to rearrangement, also fomed a pyran in good yield. Significantly, the catalyst was shown to tolerate the presence of water.
Kyohei Fujiwara, Takuya Kurahashi, and Seijiro Matsubara, J. Am. Chem. Soc. 2012, 134, 5512−5515
Proximal Ligand Electron Donation and Reactivity of the Cytochrome P450 Ferric−Peroxo Anion
Cytochrome P450 enzymes, also called CYPs, are heme proteins with unusual cycteine-derived axial thiolate ligands that catalyze a wide variety of biological oxidations. In humans so-caled phase I metabolism of drugs results from P450-mediated oxidations. However, thousands of P450 proteins have been identified throughout biology that oxygenate all sorts of organic compounds compounds, including fatty acids, steroids, and xenobiotics. For a vast majority of bacterial P450s the subsrates and functions remain unknown. Some, such as EryF, are known to be involved in the biosynthesis of antibiotics, while others, such as P450cam (CYP101) are involved terpene catabolism.
CYP125 from Mycobacterium tuberculosis catalyzes the conversion of the terminal side-chain methyl group of cholesterol to various oxygenated states, alcohol, aldehyde and carboxylic acid. Paul R. Ortiz de Montellano and his group at UC San Francisco have recently reported that that CYP125 also the deformylation of the sterol side chain. The aldehyde intermediate is shown to be the precursor of both the conventional acid metabolite and the five deformylation products. These deformylation products are thought to arise from a reaction of the aldehyde intermedaite with a deprotonated ferric-peroxo intermediate, (heme)Fe(III)-O-O-. Replacement of the coordinating cysteine sulfur with selenium led to a product distribution with less of the deformylation products and more terminal side chain carboxylic acid. The results are interpreted to derive from an increase in the pKa of the ferric− peroxo anion in the selenium derivative as compared to the natural cysteine sulfur coordination.
In the early stages of MTb infection, the bacterium invades the aveolar macrophage (white) cells of the lung. These are the very cells usually responsible for bacterial killing and general house keeping. Remarkably, however, MTb is able to disable the bacteriocidal activities of the aveolar macrophage and propagate within the host cell. Once ensconced within the host, MTb uses cholesterol derived from the host as food. Furthermore, the steroid nucleus is then tailored by various oxidizing proteins in the bacterium to extend its control over the host cell. Studies such as these that reveal the pathways used by MTb to manipulate cholesterol may reveal drugable targets to help control this terrible disease.
Santhosh Sivaramakrishnan, Hugues Ouellet, Hirotoshi Matsumura,Shenheng Guan, Pierre Moënne-Loccoz, Alma L. Burlingame,and Paul R. Ortiz de Montellano, J. Am. Chem. Soc. 2012, ASAP, published on-line March 23, 2012. DOI: 10.1021/ja211499q
HepatoChem Presents at Early Stage Technology Event
UMASS MATTC Center’s VII Annual Event Features HepatoChem
Marc Bazin, CEO President, and Co-Founder, HepatoChem presented at the UMASS MATTC Center’s VII Annual ‘The Early-Stage Life Sciences Technology Conference’ on Thursday, April 12, 2012 at the Merck Research Laboratories to over 200 angel investors, venture capitalists and corporate investors. For more information…..
Nucleus Article About HepatoChem Reachs the Greater Boston ACS Community
In a recent article of the Nucleus, the newspaper of the New-England ACS section, HepatoChem’s president was interviewed. You can find this article on the NE-ACS website. For more details – http://www.nesacs.org/
For more information contact:
Shelley Amster, Director Business Development, HepatoChem
Phone: (978) 371-5901
Mobile: (978) 239-1468