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Monthly Meeting A First-Time Mentor Joint Meeting with BAGIM NEBHE Science Network by Jin Ji Chair’s Statement Summer Research Scholar By Mukund Chorghade Design and Synthesis of Novel Inhibitors of Dihydroorotase 2007 Chair’s Statement By Mukund Chorghade It is a singular honor and privilege to ing several prominent scientists has between the medicinal and process assume the office of Chair for the been arranged on March 30. This could chemistry groups and facilitate via Northeastern Section. The breadth, be the forerunner of an annual Life Sci- symposia and discussion groups new depth and sophistication of the talent ences Symposium and could provide a perspectives on the progress of a drug and creativity of the individuals in the useful forum for productive exchange from conception to commercialization. section are truly outstanding. We have of ideas. (2) Encourage a vitalized (5) Organize a few lunch time lectures eminent researchers and professionals speakers bureau to provide guest lec- to attract researchers who, because of representing the strategic triad of aca- tures to schools, universities and civic their busy schedules, are not able to demia, government and industry from and community groups. The topics can attend the evening lectures. The ACS all sub-disciplines of chemistry. We encompass issues of topical interest, has novel programs like the science enjoy a cherished and hallowed tradi- e.g., chemical safety, environmental café’s that will be of great interest to tion of excellence. The warmth and and the contributions made by our members. (6) Increase participa- gracious hospitality with which we chemists/chemistry to the benefit of tion of members in the section activi- welcome participation by our mem- society at large. (3) Expand the activi- ties and increase the membership of bers, collaborators and distinguished ties of the Professional Training/Educa- the ACS and the section. This will also guests has been the hallmark of our tion and Career Services committees. allow greater opportunities for net- tradition and the well-spring of our Regular workshops will be used to edu- working among chemists. Greater progress cate students at local colleges/universi- emphasis will be placed on attracting It will be my endeavor to (1) Fos - ties and mid-career professionals about chemists in the biotechnology / bio- ter greater interactions between the the diverse opportunities in chemistry, pharmaceutical industries and partici- ACS and the other professional bodies current trends in globalization, resume pation of their employers via corporate catering to the cause of chemistry - writing, interviewing skills/techniques sponsorships (7) Stimulate additional The American Institute of Chemists and related topics. Such workshops participation of the section in the inter - and the International Union of Pure will also benefit mid-career and national activities of the ACS. Our and Applied Chemistry come readily to chemists undergoing a career transi- members are involved in a wide array mind. A one-day joint meeting featur- tion. (4) Build a much-needed bridge continued on page 16
2 The Nucleus January 2007 The Northeastern Section of the American Chemical Society, Inc. Contents Office: Marilou Cashman, 23 Cottage St., Natick, MA 01360. 1-800-872-2054 (Voice or FAX) or 508-653-6329. 2007 Chair's Statement ______2 e-mail: mcash0953(at)aol.com Any Section business may be conducted By Mukund Chorghade via the business office above. NESACS Homepage: Grants-In-Aid and Career Services 4 http://www.NESACS.org ______Sathish Rangarajan, Webmaster ACS Hotline, Washington, D.C.: Monthly Meeting ______5 1-800-227-5558 Joint with BAGIM, Yvonne Martin to Speak on "Lessons from 41 Years as a Officers 2007 Computational Chemist" Chair: Mukund Chorghade 14 Carlson Circle, Natick, MA 01360 Second Heyn Book Award______6 508-651-7809 and 308-3891 Chorghade(at)comcast.net A First-Time Mentor 6 Chair-Elect: ______Marietta Swartz NEBHE Science Network by Jin Ji Chemistry Department, Umass-Boston Boston, MA 02125 Report from Seoul 7 617-287-6146; marietta.swartz(at)umb.edu ______Immediate Past Chair: By Morton Z. Hoffman Patricia Mabrouk Chemistry Department, Northeastern University Summer Research Scholar 8 Boston, MA 02115 ______613-373-2845; p.mabrouk(at)neu.edu Design and Synthesis of Novel Inhibitors of Dihydroorotase by Secretary: Kerry Heinzelmann and Evan Kantrowitz Michael Singer Sigma-Aldrich 3 Strathmore Rd., Natick, MA 01360 National Chemistry Week Report ______10 508-651-8151X291; msinger(at)sial.com Treasurer: Connections to Chemistry ______11 James Piper 19 Mill Rd., Harvard, MA 01451 978-456-3155, piper28(at)attglobal.net Cover: From L-R: Evan Heyn, Mary Mahaney, Chair of the NESACS Board of Auditor: Publications, Vincent Gale, Advertising Manager of the Nucleus and recipient of Anthony Rosner the second Arno Heyn Memorial Book Award, Michael P. Filosa, Editor of the Archivist: Myron S. Simon Nucleus, Vivian Walworth, Board of Publications, Robert Heyn and Janice Heyn. 20 Somerset Rd. Newton, MA 02465; 617-332-5273 Deadlines: March 2007 Issue: January 10, 2007 Romysimon(at)mindspring.com Trustees: April 2007 Issue: February 12, 2007 Joseph A. Lima, Esther A. H. Hopkins, Michael E. Strem Councilors Alternate Councilors Term Ends 12/31/2007 Thomas R. Gilbert Arlene W. Light Michael J. Hearn Timothy B. Frigo The Nucleus is distributed to the members of the Northeastern Section of the American Chemical Michael Singer Mary Mahaney Society, to the secretaries of the Local Sections, and to editors of all local A.C.S. Section publications. Pamela Nagafuji Mark Froimowitz Forms close for advertising on the 1st of the month of the preceding issue. Text must be received by the Term Ends 12/31/2008 editor six weeks before the date of issue. Doris I. Lewis Patrick M. Gordon Morton Z. Hoffman Michael P. Filosa Editor: Michael P. Filosa, editor, Ph.D., ZINK Imaging Incorporated, 1265 Main Street, Christine Jaworek-Lopes Lawrence Scott Waltham, MA 02451 Email: Michael.Filosa(at)zink.com; Tel: 781-386-8479. Mary Burgess Liming Shao Associate Editors: Myron S. Simon, 20 Somerset Rd., W. Newton, MA 02465, Tel: 613-332-5273 Donald O. Rickter S.B. Rajur Nancy Simons, Analytical Chemist, Corporate R&D, Boston Scientific Corp., Term Ends 12/31/2009 1 Boston Scientific Place A4, Natick, MA 01360-1537. Catherine Costello Julia H.Miwa Email: Nancy.Simons(at)bsci.com; Tel. 508-650-8603; Fax 508-647-2329 Patricia Mabrouk Alfred Viola Sheila E Rodman, Konarka Techologies Inc., 116 John St. Suite 12, Lowell, MA Michaeline F. Chen Wallace J. Gleekman 01852 email:srodman(at)konarka.com tel 978-569-1414 Dorothy J. Phillips Eva B. Binnun Amy Tapper Barney Grubbs Board of Publications: Mary Mahaney (Chair), Martin Idelson, Vivian K. Walworth Business Manager: Karen Piper, 19 Mill Rd., Harvard, MA 01451, Tel: 978-456-8622 All Chairs of standing Advertising Manager: Vincent J. Gale, P.O. Box 1150, Marshfield, MA 02050, Committees, the editor Tel: 781-837-0424; FAX: 781-837-1453 of THE NUCLEUS, and Contributing Editors: Morton Hoffman, Feature Editor; Dennis Sardella, Book Reviews; the Trustees of Section Calendar Coordinator: Sheila Rodman, email: srodman(at)konarka.com Funds are members of the Photographers: Morton Z. Hoffman and James Phillips Board of Directors. Any Councilor of the American Chemical Society Proofreaders: Donald O. Rickter, Myron S. Simon, Vivian K. Walworth residing within the section area is an ex officio Webpage: Webmaster: Sathish Rangarajan, sathish.rangan2(at)gmail.com member of the Board of Directors. Copyright 2006, Northeastern Section of the American Chemical Society, Inc. The Nucleus January 2007 3 Grants-in-Aid NESACS Corporate Patrons and Golf Iridium Astra Zeneca R&D Boston Awarded to Career Genzyme Drug Discovery & Dev Hovione IBM Under- Services at IRIX Pharmaceuticals Johnson-Matthey Pharma Solutions graduates Monthly Lyophilization Service of New Eng- land Merck The Education Committee has awarded Meetings Phasex Corporation Grants-in-Aid of $250 each to four The NESACS Career Services Com- Sepracor undergraduates at colleges and univer- Strem Chemicals, Inc. mittee is dedicated to providing ACS sities within the Northeastern Section Zone Enterprises Members with the best tools to manage to enable them to attend the ACS Corporate Sponsors and Golf National Meeting in Chicago, Illinois careers. We offer career guidance and focus on the components needed for Rhodium to present a paper at the Under graduate Aerodyne Research, Inc. Research Poster Session in the Division targeting the job market: personal assessment, identifying market trends, Cambridge Isotope Laboratories of Chemical Education on Monday, Cambridge Major Laboratories credentials, research and networking. March 27, 2007. Matching funds have New England BioLabs, Inc. been committed by the institutions to We have a comprehensive (lecture, Pfizer support the students’ travel. The recipi- demo and review) program that pro- Sigma-RBI ents are also required to participate in vides assistance in writing winning Shasun Pharma Solutions the Northeast Student Chemistry resumes and cover letters as well as various techniques and skills needed Donors and Golf Tungsten Research Conference (NSCRC) in Consulting Resources Corp. April 2007. for a successful interview. Dishman Pharmaceuticals In collaboration with the Speaker’s The awardees, their research supervi- And Chemicals Limited Bureau, we will organize a program of sors, and the titles of the papers are as Houghton Chemical Company resume reviews and short lectures follows: Organix, Inc. focusing on current topics at Section Vertex Richard Hughes, Jr., Boston College, Meetings. Two distinguished recruiters (Prof. Lawrence Scott) Towards the in our area, Megan Driscoll and Jen- Synthesis of Arm-Chair Carbon Nan- nifer Sass of PharmaLogics Recruiting, otubes will join me in offering valuable per- Wallace J. Paresh Agarwal, Massachusetts Insti- spectives and 1:1 career counseling to tute of Technology (Prof. Christopher members. These sessions will typically Cummins ) An Isolable and Monomeric be held between 2:30 pm and 4:30 pm. Gleekman Phosphorous Radical that is Reso- Members will be able to benefit from The Editor of the Nucleus is sad- nance-Stabilized by the Vanadium such networking: this will be a regular dened to report the death of long-time (IV/V) Redox Couple feature of Section Meetings in 2007. NESACS stalwart and retired Brook- In general our members have pro- line High School teacher, Wally Taryn Palluccio, Bridgewater State vided positive feedback. Reproduced College (Prof. Stephen Waratuke) Gleekman on November 23, 2006. A below are comments from one member more complete remembrance will be Hydroaminations of Alkynes, Enynes who benefited from our programs: and Dienes Using Titanium Catalysts published in a future issue. MPF ◆ “My career counseling session with Dr. Chaoyuan Kuang, Massachusetts Insti- Chorghade began with some basic attended many workshops. The assis- tute of Technology (Prof. Graham questions designed to engage me and tance that I received through ACS Walker) Regulation of Activity of E.coli focus me on clearly stating my objec- career services has been the most Proteins UmuC and UmuD tives. The process of reviewing my CV knowledgeable and helpful that I have Applications for the travel stipend are began with an examination of its over - experienced. While the improvements accepted from students majoring in all structure and an assessment of the to my CV are significant, the feedback chemistry, biochemistry, chemical engi- impression of prospective screeners. I received on my qualifications and neering, or molecular biology who are This overview was followed by a search strategies was profound. The in good standing with at least junior detailed review focused on content, best part of the process is the quality of status, and are currently engaged in wording and vocabulary. I have read assistance and sincere caring of the undergraduate research. ◆ several books on resume writing and counselor.” ◆
4 The Nucleus January 2007 Monthly Meeting Biography The 875th Meeting of the Northeastern Section of the American Chemical Society Jointly with the Boston Area Group for Informatics and Modeling (BAGIM) Thursday – January 18, 2007 Harvard Faculty Club, 20 Quincy St., Cambridge, MA. Yvonne Martin retired at the end of October from her position as Senior 2:30 pm Career Services Presentations and Resume Reviews, Mukund Research Fellow, Volwiler Society, Chorghade, Chair, NESACS; Megan Driscoll and Jennifer Sass of Abbott Laboratories. Her research PharmaLogics Recruiting. interests include strategies for increas- 4:30 pm Board Meeting ing the molecular diversity of com- pound collections; to triage hits from 5:30 pm Social Hour HTS; to predict the potency, binding 6:30 pm Dinner affinity, or absorption, distribution, metabolism, and excretion (ADME) 8:00 pm Evening Meeting, Dr. Mukund Chorghade, Chair, presiding properties of small molecules from Dr. Yvonne Connolly Martin, Senior Research Fellow (retired), their molecular structures; and for the Volwiler Society, Abbott Laboratories. computer design of novel compounds Lessons from 41 Years as a Computational Chemist including 3D database searching, de novo design, and pharmacophore map- Dinner reservations should be made no later than noon, Thursday, January 11, ping. Dr. Martin did her undergraduate 2007. Please call or fax Marilou Cashman at 800-872-2054 or e-mail at work in chemistry and biology at Car - Mcash0953(at)aol.com. Please specify vegetarian. Reservations not cancelled at leton College, Northfield, Minnesota least 24 hours in advance must be paid. Members, $28; Non-members, $30; and her PhD work in chemistry at Retirees, $15; Students, $10. Northwestern University focusing on physical biochemistry. Her entire THE PUBLIC IS INVITED career (40+ years), except for a stay Anyone who needs special services or transportation, please call Marilou Cash - with Corwin Hansch, has been at man a few days in advance so that suitable arrangements can be made. Free Abbott Laboratories; the past 35 years parking in the Broadway St. Garage (3rd level or higher). Enter from Cam- involving various aspects of computer- bridge Street via Felton Street. assisted drug design. She is a member of the Advisory Board for the QSAR and Modeling Society, an editor for the publication “Perspectives in Drug Career Abstract Design and Discovery” and a section editor for “QSAR: Annual Reports in Lessons from 41 Years as a Computational Chemistry”. Dr. Martin Services Computational Chemist is on the editorial boards for “The Journal of Computer Aided Molecular Are you interested in changing jobs? This talk will address the following Do you wonder whether your inter- Design” and “QSAR & Combinatorial questions: how many ways can a com- Science” and is a former member of viewing abilities could be enhanced? putational chemist impact the effi- Could your resume use some work? If the NIH Biodata Management and ciency of drug discovery? Do models Analysis Study Section. Honors yes, please join us at the January always have to be accurate to be use- meeting, where you can receive advice received include Phi Beta Kappa; NIH ful? Are there other ways that a com- pre-doctoral fellow; AAAS fellow; from industry professionals. putational chemist can impact drug Topics and services which we will IUPAC fellow; life-time member of the discovery than by developing or using Molecular Graphics and Modeling cover: how to put together an eye- quantitative or 3D molecular model- catching resume, best interviewing ◆ Society; and the Accomplishment ing? Award, The Society for Biomolecular strategies, and how to find the most ◆ appropriate opportunities ◆ Sciences (2005). The Nucleus January 2007 5 2nd Heyn A First-Time Mentor By Jin Ji, PhD Book Award Chairperson, Speakers Bureau of NESACS Our story begins at the Annual Long- Emorcia described how much impact Prize to Range Planning Meeting of the North- and guidance the events in the past had east Section of American Chemical offered to the students. She als o Society (NESACS) back in June of stressed that with more and more stu- Vincent Gale 2006. As the new chairperson of the dents attending the event each year, The second Arno Heyn Memorial Speakers Bureau of NESACS and a NEBHE was constantly looking for Book Prize Award was made to long- new board member of NESACS, I was qualified experts and professionals in time Nucleus Advertising Manager, attending my first Long-Range Plan- these fields to be inspiring mentors. Vincent Gale. Vince has served the ning meeting. The purpose of the meet- “That’s interesting!” I thought to Nucleus for sixteen years. He was ing was twofold: to encourage myself, “Introducing students to the recruited by former Nucleus Editor, communications among many commit- possibilities of a career in chemistry or Arno Heyn when Arno recreated the tees within NESACS, and to stimulate chemistry-related sciences is exactly Nucleus in the form it has today. Vince dialogue between NESACS and other what our Speakers Bureau should be is also the advertising manager for a organizations in the New England area. doing! That’s something we definitely number of other newsletters published I wondered to myself, “How will this should take part in.” After Emorcia by ACS Sections including The Indica- meeting impact the Speakers Bureau’s spoke, I introduced myself and we tor, The Vortex, The Catalyst, The Cru- activities?” decided to discuss further the collabo- cible, The Del-Chem Bulletin and The NESACS wanted to establish an rations between our two organizations. Capital Chemist. Vince also maintains active outreach committee whose goal The planning went smoothly. I a website to manage and promote was to bridge the chasm between sent out a solicitation within the bureau advertising in the aforementioned chemistry and the public. The out- and three speakers, Mukund ACS sectional newsletters: www. come: a Speakers Bureau was created Chorghade, Robert Litman and mboservices.net. and the NESACS Chair , Dr. Pam Michael Filosa, responded with posi- The prize was presented at the Mabrouk, appointed me its chairperson tive feedback. They were all enthusias- November meeting held at UMASS starting in January 2006. The idea was tic about becoming advisors for the Boston by Board of Publications mem- to organize volunteer speakers, who as event. Susan Bryant, the coordinator ber and long-time friend of Arno Heyn, experts and professionals in chemistry of the event, was very appreciative of Vivian Walworth. In attendance from fields could speak to schools, indus- Speakers Bureau’s participation and the Heyn family were Arno’s sons tries and different communities and mentioned that NEBHE hoped “to con- Evan and Bob, also present was Bob’s organizations about the benefits of our tinue working with the Speakers wife, Janice Heyn. Last year’s recipi- profession. The events would be free Bureau in the future.” ents of the first Arno Heyn Prize were to the audience. Six months into build- Saturday, November 18th, 2006, former Nucleus editor, Mark Spitler ing the bureau, the bureau had would be an interesting day for the and former NESACS Webmaster, Sam attracted twelve passionate profession- many students and mentors who partic- Kounaves. MPF ◆ als and willing speakers. We had even ipated in the Science Network at MIT planned a series of career counseling – and a delightful day for Robert Lit- events at monthly NESACS meetings man, Michael Filosa and myself who What’s Yours? starting in September. But what else? had the honor of representing the DMPK Scientist, At the Long-Range Planning bureau. The event was full of young LC/MS Product Specialist, meeting, besides the board members curious minds, lots of energy and an Mass Spec Operator, that I often saw at regular monthly abundance of excitement when it came Staff Investigator, board meetings, I noticed a few new to learning about careers in science, Process Chemist, faces. One of them was Emorcia Hill technology and engineering. They had QA Manager, from New England Board of Higher endless questions. Synthetic Chemist, Education (NEBHE). She discussed All the mentors and advisors were Lab Instructor an annual event that NEBHE was divided into different groups and Many local employers post positions organizing – the Science Network at matched with students who have spe- on the NESACS job board. MIT on November 18th, 2006 which is cific interests in their fields. Having an event to introduce college and high been working in biochemical fields Find yours at school students who are interested in and developing medical devices, I was www.nesacs.org/jobs sciences and technologies to peers and assigned to be a mentor for a group of to inspiring mentors in these fields. continued on page 16
6 The Nucleus January 2007 REPORT FROM SEOUL Morton Z. Hoffman, Boston University
The Nucleus January 2007 7 Summer Scholar Design and Synthesis of Novel Inhibitors of Dihydroorotase by Kerry Heinzelmann, Advisor: Evan Kantrowitz, Boston College Department of Chemistry, Merkert Chemistry Center, Chestnut Hill, MA 02467 Dihydroorotase (DHOase) is the second enzyme in pyrimi - fore, since P. falciparum does not have a salvage pathway dine nucleotide metabolism; it catalyzes the reversible ring for pyrimidine nucleotides, inhibitors of P. falciparum closure of N-carbamoyl-L-aspartate (CA) to form dihy- DHOase have the potential to have anti-malarial activity. droorotate (DHO). The active site of DHOase was found to be a pocket within a pocket. When DHO binds to the enzyme, it binds to the lower pocket, adjacent to the Zn 2+ ions, leaving the hydrophobic upper pocket empty. Because the upper pocket remains empty, a potential inhibitor of DHOase may bind to this upper pocket, or it may expand off of the substrate to fill the upper pocket. A virtual screening system developed in the Kantrowitz lab was used to identify potential inhibitors of DHOase by docking a library of compounds to the active site with and without DHO bound. Identified DHOase is a member of the amidohydrolase superfam - compounds were evaluated kinetically and used to design ily of enzymes. The mechanism of the enzymes in this second generation inhibitors. superfamily involve Zn2+ ions.1 In mammals, DHOase is Results part of the multifunctional enzyme CAD along with aspar - tate transcarbamoylase and carbamoyl phosphate synthetase, Identification of possible DHOase inhibitors but in bacteria DHOase is an independent enzyme.2 The As a means to identify an entirely new classes of structure of homodimeric E. coli DHOase has been deter- inhibitors we used a virtual screening that allows for the mined, and the active site was shown to contain two Zn 2+ rapid evaluation of interactions between an enzyme active ions.3 In the determined structure one active site contains site and small molecule compounds. This was accomplished CA and the other contains DHO (see Figure 1). computationally using available docking programs. Optimization of virtual screening for DHOase Because of the different algorithms used, a specific docking program may be better suited for a particular tar get active site. Therefore, we tested three programs to see which would be the best for DHOase. The three programs tested were AUTODOCK3,5 DOCK56 and SURFLEX.7 Program optimization was performed on DHOase with the substrate carbamoyl aspartate bound in one active site and the product DHO bound in the other (PDB entry 1J79 3). The molecule in the active site was removed and its coordi - nates changed so that it was in a different spatial position, unrelated to the actual binding site. The DHO or CA was then docked into the active site using AUTODOCK3, Figure 1. Structure of homodimeric E. coli DHOase (PDB entry 1J79). DOCK5 and SURFLEX. The RMS deviation between the The structure of each monomer is organized as a “TIM” barrel. The prod- DHO from the X-ray structure and the best conformer from uct DHO is shown in the right active site, while the substrate CA is shown AUTODOCK3 was 0.36 Å, 0.49 Å for DOCK5 and 3.5 Å 2+ in the left active site. The two Zn ions in each active site are also shown. for SURFLEX. The large RMS deviation with SURFLEX was due to its inability to position the carboxylate in the The DHO from the malaria parasite ( P. falciparum) and proper orientation. Therefore AUTODOCK3 was selected to E. coli DHOase have 27.5% conserved residues, including be used to identify new inhibitors (see below) all residues involved in catalysis and metal binding. This suggests that the active site structure of P. falciparum Identification of new inhibitors of DHOase by vHTS DHOase is similar to the structure of E. coli DHOase, and All of the compounds in the Sigma-Aldrich catalog that their catalytic mechanisms are the same. Seymour et were docked to the DHO site in DHOase using al.4 have shown that an inhibitor of DHOase results in the AUTODOCK3. The two compounds that gave the best accumulation of carbamoyl aspartate and an overall results from the docking were 1 and 2. decrease in the formation of pyrimidine nucleotides. There- continued on page 9
8 The Nucleus January 2007 Summer Scholar including consistently low yields of the desired oxidation product, and formation of undesirable side products. Continued from page 8 Because of the problems with the synthesis of 3, structurally similar compounds that were commercially available and showed binding affinity for the enzyme were considered as base units instead. We are currently using one such com- pound, 1,3,5-cyclohexanetricarboxylic acid 4, as a base unit for synthesis of potential inhibitors. As seen in Figure 3, two of the carboxylic acids of 4 are initially benzyl pro- tected using 2 equivalents of benzyl alcohol. An amine is then coupled to the unprotected carboxylic acid in the pres - ence of DCC, HOBt, and Et 3N. Finally, after the two acid groups are deprotected by catalytic hydrogenation, another Compounds 1 and 2 amine can be coupled to one acid group by using the same coupling conditions. Ability of 1 and 2 to inhibit DHOase (e) Future directions 1 and 2 were tested for their ability to inhibit DHOase. Reactions were setup at sub-saturating concentrations of DHO, and in the absence and presence of increasing con- centrations of either 1 or 2. As seen in Figure 2, 1 was not able to inhibit DHOase over the concentration range tested, while 2 exhibited significant inhibition.
Figure 3. Synthesis using the 1,3,5-cyclohexanetricarboxylic acid, 4, base unit. (a) CDI, Benzyl alcohol, rt 24 h; (b, d) DCC, HOBt and Et3N; (c) 10% Pd/C, CH3OH, 18 h. This project is being continued during the current aca - demic year as part of an undergraduate research project. Currently, a series of molecules with compound 4 as their base unit are being synthesized. AUTODOCK was used to help select the R groups that would enhance binding to DHOase. Once these syntheses are complete, the com- pounds will be assayed to determine their ability to inhibit DHOase. In the future, we plan on synthesizing compounds Figure 2. Inhibition of DHOase by inhibitors 1 (circles) and 2 (squares). with 1,3,5-benzenetricarboxylic acid 5 as the base unit, and comparing the inhibition of these compounds to those con - Modifications to the structure of 2 taining 4. Experimental Procedure Enzyme purification The plasmid that contained the gene for E. coli DHOase (obtain from Frank Raushel, Texas A&M Univer- sity) was transformed into a special E. coli strain that can be induced to produce T7 polymerase. The strain/plasmid com- Compounds 3, 4 and 5 bination was grown in YT media at 37°C until the A600 Modifications of 2 were docked in order to optimize the reached 0.6, at which time 0.4 mM IPTG was added to inhibitory effects on DHOase. Molecules with different induce the production of the enzyme. After overnight base units (3, 4, 5) were examined, with the R groups repre - growth, the cells were harvested by centrifugation followed senting different cyclic amines and then docked to check by sonication to break open the cells. Ammonium sulfate their respective affinity for the active site. The base unit was added to the clarified lysate to 60% saturation. The pre- most like the substrate, 2-oxohexahydropyrimidine-4,6- cipitate, containing the protein, was dissolved in buf fer (50 dicarboxylic acid, 3, was selected for the synthesis of the mM Tris-phosphate, 100 µM ZnCl2), then dialyzed against first set of compounds. Compound 3 was not commercially the same buffer. Anion-exchange chromatography was then available, however its synthesis had been previously used to purify the DHOase using Source Q resin (GE Heath- 8 reported. Problems occurred during the synthesis of 3 continued on page 10
The Nucleus January 2007 9 Summer Scholar paradigm for catalysis through the use of a binuclear metal center. Biochemistry National Continued from page 9 2001, 40, 6989-97. Care). The column was eluted with a 4. Seymour, K. K.; Lyons, S. D.; Phillips, gradient of NaCl in the above buffer. L.; Rieckmann, K. H.; Christopherson, Chemistry Fractions containing enzyme were R. I. Cytotoxic effects of inhibitors of de combined and checked for purify by novo pyrimidine biosynthesis upon Plas- modium falciparum. Biochemistry 1994, Week Report SDS-gel electrophoresis. 33, 5268-74. By Christine Jaworek-Lopes Enzyme activity determination 5. Goodsell, D. S.; Morris, G. M.; Olson, The activity of the DHOase in the A. J. Automated docking of flexible lig- Approximately 3000 individuals absence and presence of inhibitors was ands: applications of AutoDock. J Mol learned about NCW through the events determined by measuring the initial rate Recognit 1996, 9, 1-5. held this year. The breakdown was as of the reaction in the reverse direction. 6. Shoichet, B. K.; Bodian, D. L.; Kuntz, I. follows: ~450 individuals attended the The amount of N-carbamoyl-L-aspar- D. Molecular docking using shape kick-off event at Wellesley College, tate formed was determined colorimet- descriptors. J. Comp. Chem. 1992, 13, ~1500 individuals visited the Chil- rically as previously reported.9 380-397. dren’s Museum and ~1000 individuals 7. Jain, A. N. Surflex: fully automatic flexi- visited the MOS on October 28, 2006. References ble molecular docking using a molecular Over 100 volunteers from 12 different 1. Nam, S. H.; Park, H. S.; Kim, H. S. Evo- similarity-based search engine. J Med organizations (ACS members, Phyllis lutionary relationship and application of Chem 2003, 46, 499-511. A. Brauner Memorial Committee, a superfamily of cyclic amidohydrolase 8. Adams, J. L.; Meek, T. D.; Mong, S. M.; enzymes. Chem Rec 2005, 5, 298-307. Emmanuel College, Gordon College, Johnson, R. K.; Metcalf, B. W. cis-4- Malden High School, Mass General 2. Lee, L.; Kelly, R. E.; Pastra-Landis, S. Carboxy-6-(mercaptomethyl)-3,4,5,6- C.; Evans, D. R. Oligomeric structure of tetrahydropyrimidin-2(1 H)-one, a potent Hospital, Merck Chemical Company, the multifunctional protein CAD that ini- inhibitor of mammalian dihydroorotase. Northeastern University, Simmons tiates pyrimidine biosynthesis in mam- J Med Chem 1988, 31, 1355-9. College, Suffolk University, Tufts Uni- malian cells. Proc Natl Acad Sci U S A 9. Pastra-Landis, S. C.; Foote, J.; versity, Wellesley College) contributed 1985, 82, 6802-6. Kantrowitz, E. R. An improved colori- to the successful week. 3. Thoden, J. B.; Phillips, G. N., Jr.; Neal, metric assay for aspartate and ornithine The NCW committee would like T. M.; Raushel, F. M.; Holden, H. M. transcarbamylases. Anal. Biochem. 1981, to offer Salutes to Excellence Awards Molecular structure of dihydroorotase: a 118, 358-363. ◆ to the following: Merck Chemical Company for financial support of the events as well as providing all the materials for the chromatography demonstration performed at the MOS- Boston, Boston Children’s Museum, Museum of Science-Boston, and Wellesley College. As of November 14, 2006, only two puzzle solutions and no posters were submitted as part of the contest. NCW 2007 will be from October 21 – October 27, 2007. The theme is “The Many Faces of Chemistry.” The kick-off event on October 21 will be held at the Museum of Science as well as an outreach event on October 22. A third event will be held at the Chil- dren’s Museum on October 27. ◆
10 The Nucleus January 2007 Report from Seoul Connections to Chemistry Continued from page 7 Åkesson (Sweden), Margaret-Ann By Ruth Tanner Armour (Canada), Peter Atkins (U.K.), The Connections to Chemistry program clubs. (Her office donated 150 of the Karl Brachtl (Austria), Marianne Cutler took place at Burlington High School canvas CHED bags for the program (UK), Morton Hoffman (USA), Onno (Burlington, MA) on Wednesday, Octo- from the BCCE program held at Pur- De Jong (Netherlands), Mordechai ber 18th, 2006, 3:30 –8:00 PM. Each due University this past summer.) Dr. Livneh (Israel), Jim McQuillan (New registrant participated in two of the Daniel Nocera, Professor of Chemistry Zealand), Mauro Mocerino (Australia), five different workshops that were and W. M. Keck Professor of Energy at and Kay Stephenson (UK), chose the scheduled including a workshop on the Massachusetts Institute of Technol- winning posters in the two age cate- engineering in chemistry, a National ogy gave a very spirited evening gories. The winners received certifi- Chemistry Week workshop on paints address: The Energy Future of Our cates of recognition and small and coatings, and a workshop on start- Planet which was followed by a raffle electronic devices as gifts. ing a high school chemistry club, one of American Chemical Society items Social activities associated with of the new initiatives of the Education (mugs and laser pen pointers), sub- the conference included a visit to the Division of the ACS. Terri Taylor, the scriptions to the Journal of Chemical Korean Folk Village, preceded by Manager of the ACS Office of High Education (2 of which, were donated lunch in a traditional Korean family School Chemistry in Washington wel- by the Journal) memberships in CHED roadside restaurant (leaving shoes at come the participants on behalf of the (donated by CHED), and memberships the door, seating on mats on the floor, American Chemical Society at the in CTC (Chemistry Teacher Connec- following the colorimetric rule for opening meeting and also gave the tion). ◆ spiciness [the redder the food, the hot - workshop on high school chemistry ter it is]); Participants’ Night with national songs and performances; and Heritage
The Nucleus January 2007 11 THE SPEAKERS BUREAU OF NESACS BRIDGING THE CHASM BETWEEN SCIENCE AND THE PUBLIC Mission Statement The Speakers Bureau of NESACS (Northeastern Section of the American Chemical Society) acts as a bridge between the public and science. We are a group of qualified volunteer speakers who have in depth knowledge in chemistry and related sciences and are passionate about sharing our profession with the public. We use intrigue, analogies and humor to inform the public about new strides in sciences, build awareness of sci - ence and and confront the misconceptions about our profession with knowledgeable answers
How does our volunteer, free-of- charge program work? CALL US IF: Step 1. We find out what the public wants to know by communicating with YOU ARE CONSIDERING having a speaker to various organizations such as museums, engage your group in a lively and healthy schools, and neighborhood groups. discussion on scientific topics of current interest. Step 2. We set up speaking events through these public venues at no charge YOU ARE knowledgeable in chemistry or related to your organization or your audience. sciences and passionate about sharing your Step 3. One of our knowledgeable speak- valuable knowledge with curious audiences. ers presents a scientific topic of interest and engages in a healthy discussion.
Contact Marilou Cashman at [email protected] , or Dr. Jin Ji, Chairperson of the Speakers Bureau at [email protected] , or go to www.nesacs.org/sb/home.html for more information.
Brauner Memorial Lecture October 22, 2006
Professor Bassam Z. Shakhashiri, candidate for ACS President, during his presentation of the Phyllis A. Brauner Memorial Lecture at Wellesley College on (l-r) Doris Lewis (Suffolk University), Bassam, Susan Brauner, Hyacinth Brauner. October 22, 2006. Photos by Morton Z. Hoffman
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Chair’s Statement A First-Time Mentor Calendar Continued from page 2 Continued from page 6 of activities here-the collaboration with students who had interests in medical Please check NESACS website the German Chemical Society has been fields. This was an utterly new experi- and university websites for late outstanding! Plans are well under way ence for me as I have always consid- breaking changes. for extensive collaboration with the ered myself a learner and constantly Jan 17 Indian and the Chinese Chemical Soci- identified people in my professional Milton R. Smith, III (Michigan State Univ.) eties. One of ACS’s most successful careers as my own mentors. “TBA.” mechanisms for delivering highly Many of the students in my group (Woodward Lecture Series, Harvard-MIT focused technical content in the United only knew how to get into medical Inorganic Chemistry Seminar.) States has been through the ProSpec- fields through premedical studies and MIT, Room 6-120, 4:00 p.m. tives series of conferences. The presti- Medical school. Once they found out Jan 22 gious “ProSpectives” conference will that I majored in chemistry and was Jeffery Kelly (The Scripps Research Institute) be organized at various locations in working at Harvard Medical School “TBA” India and China. developing medical devices, they began (Woodward Lecture Series, Organic Chemistry Seminar) So, dear members, please join us in probing for details: “How did you get Harvard Univer, Pfizer Lecture Hall 4:15 p.m. what promises to be an outstanding year to where you are today?”, “Were there Jan 23 of progress and additional programs. any obstacles?”, “How did you know Volunteers like you are a tremendous this was what you wanted to do?”… Prof. Anne Gershenson (Brandeis Univ.) “Single Molecule Studies of Molecular source of ideas that constitute the It made me think. I must have Mousetraps: Serpin Folding & Protease lifeblood of an organization. Join a asked similar questions when search- Inhibition” committee of your choice, provide cre - ing for a path for my life. I must still Boston College, Merkert 130 4:00 PM ative inputs into the programs and join be asking these questions in my heart, Jan 24 us in increasing the public’s awareness or out loud, but not realizing it. The Dr. William Reiff, (Northeastern Univ.) and enjoyment of Chemistry. ◆ answers to these questions are helpful “TBA” to the people who asked the questions, Northeastern Univ. Hurtig Hall Rm 129 12 Noon also those who through their hearts Jan 30 answered the questions. It was a day Prof Gregory Petsko (Brandeis Univ.) reflecting as well as advising. It was a “Structural Neurology: A New Approach to the day in which so many promising stu- Understanding, Treatment and Prevention of Neurodegenerative Diseases” All notices for the Calendar dents learned about us, our work and, ◆ Boston College, Merkert 130 4:00 PM should be sent to their future. Sheila Rodman Jan. 31 Konarka Technologies, Inc. Dr. Elena Rybak-Akimova (Tufts Univ.), 116 John St., Suite 12 “TBA” Lowell, MA 01852 UMass Dartmouth;Building Group II, Room 115 srodman (at) Konarka.com 4:00 PM