January 2015 Daniel Romo, Professor & Director of the Natural Products LINCHPIN Laboratory [***Moving to Baylor University, August 2015***] Synthetic, Biomechanistic, and Biosynthetic Studies of Bioactive Natural Products (Chemical Biology); Asymmetric Synthesis, Novel Transformations, and Applications of β -Lactones (Synthetic Methodology); Natural Product Mode of Action Studies (Chemical Genetics) Rm 304, (979) 845-9571, "[email protected]", FAX (979) 862-4880; WEB page: http://www.chem.tamu.edu/rgroup/romo At the heart of our research interests is the chemistry and biology of natural products. These are unique and often structurally complex molecules that are designed to interact in highly specific ways with various cellular receptors and by homology those found in humans. Thus, all our projects begin with natural products encompassing development of novel synthetic strategies towards these naturally occurring compounds or derivatives that in turn serve as useful leads for inquiries into cell biology. ‘Bioactivity-guided Retrosynthesis.’ This is a new approach toward the pursuit of natural product total synthesis that enables a synthetic chemist, if interested, to get involved with MS-based methods for activity based proteomic profiling at the early stages of the total synthesis effort. Natural products in this category that are currently being pursued include oxazolomycin and the gracillins. (No papers in this area yet, however we are preparing our initial paper that describes this new strategy for total synthesis. In addition, our recently described Diels-Alder Lactonization organocascade is being applied to the gracillins. Thus, we attempt to make use of our methodology to access natural products that we in fact plan to pursue further in terms of biological studies. In this case, toward activity based proteomic profiling with these electrophilic natural products and as a further application of bioactivity-guided retrosynthesis. Biological studies of the gracillins and spongiolactone/oxaxolomycin are supported by excellent collaborations with Prof. Luis Botana (Spain) and Prof. Stephan Sieber (Germany), respectively. Exploiting the potential of chiral unsaturated acylammonium salts. We recently discovered and are continuing to mine the rich potential of this readily available chiral intermediate readily derived from commercially available acid chlorides and catalysts. Numerous other organocascade processes are waiting to be discovered that make full use of the triple reactivity of this versatile intermediate! Computational studies in collaboration with Prof. Dean Tantillo (UC Davis) and mechanistic studies (e.g. In situ IR, LC- MS) are being pursued in conjunction with our methodological studies. •Mass Spectrometry Based-Profiling of the Cancer Proteome with Anticancer Natural Products. Using numerous cancer cell lysates that are now commercially available, we will study the interactions of several, putative natural product-based covalent modifiers of cellular proteins that are being synthesized in the lab. These in vitro experiments will provide initial data regarding protein targets of these natural products. Further experiments to validate these targets including the use of isotopically labelled proteomes (SILAC) and over-expression of putative targets in cell lines will be conducted in the laboratories of collaborators and students would have the opportunity to visit for short stays (e.g. with Prof. Jun Liu, Johns Hopkins University, Dept. of Pharmacology or Prof. Stephan Graduate Students Christian Chalheine Mikail Abbasov Weixu Kong Natalie Harvey Khoi Van Yongfeng Tao Post-Doctoral Students Dr. Paul Gladen Dr. Morgan Jounneau Dr. Sreekumar Vellalath LINCHPIN Lab: Dr. Ken Hull (co-Director) Dr. Mingzhao Zhu Dr. Haoran Xu Dr. Omar Robles TAMU Undergrad MiniPharma Protein Conjugation Group: Wali Kahn (Group and Team Ldr), Lorna Min; Molecular Modeling Team: Emily Brackhahn (Group Ldr), Asuka Orr, Adam Burkhard; Synthesis: Julia Taylor (Team Ldr), Kacey Ortiz Fungal Group: Jennifer Cuaderes (Group Ldr); Hannah Bolton, Lauren Davis (intern). N N H N N H 2 N O N HN Cl NH 2 H H 2 N palau'amine HO N NH HN HN Cl OH NHR MeO HN NH NHR axinellamine D (R = 2,3-dibromoacylpyrrole) H H H O H O H O H OH CO 2 Me H H OH rameswaralide •anti-inflammatory agelastatin A •Antitumor/cytotoxic agent N O Me H OH O Me H N MeO Me OH O Me Me Me N O OH oxazolomycin A O scabrolide A O H O OH H Me O O H H H Me OH H Me HO O H Me O O H zedoarondiol H Me OMe H HO HO Me O O chinesin II N NH O O O H N O NH HO O HO O O O N NH 2 NH 2 O O HO suomilide O OCH 3 O 3 SO Current Natural Product Topics (Synthesis and Biology) in the Romo Group R = H N O Br Br O H OC(O)CH 2 CH(CH 3 ) 2 spongiolactone O caulolactone A •antitumor/antibiotic Me O H H OAc Me Me Me OAc gracilin A N NH NH N O Me HO Br O H H H Me Me Me O H H O O OAc H Me tetrahydroaplysulphurin-1