{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:17:47Z","timestamp":1791220667312,"version":"4.1.0"},"reference-count":43,"publisher":"American Chemical Society (ACS)","issue":"4","license":[{"start":{"date-parts":[[2015,4,6]],"date-time":"2015-04-06T00:00:00Z","timestamp":1428278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/pubs.acs.org\/page\/policy\/authorchoice_termsofuse.html"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM089732"],"award-info":[{"award-number":["GM089732"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002429","name":"Amgen","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100002429","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,4,21]]},"abstract":"<jats:title>Conspectus<\/jats:title>\n                  <jats:p>Natural products chemistry has historically been the prime arena for the discovery of new chemical transformations and the fountain of insights into key biological processes. It remains a fervent incubator of progress in the fields of chemistry and biology and an exchange mediating the flow of ideas between these allied fields of science. It is with this ethos that our group has taken an interest in and pursued the synthesis of a complex family of natural products termed the dimeric epipolythiodiketopiperazine (ETP) alkaloids. We present here an Account of the highly complex target molecules to which we pegged our ambitions, our systematic and relentless efforts toward those goals, the chemistry we developed in their pursuit, and the insight we have gained for their translational potential as potent anticancer molecules.<\/jats:p>\n                  <jats:p>The dimeric ETP alkaloids are fungal metabolites that feature a highly complex molecular architecture comprising a densely functionalized core structure with many stereogenic centers, six of which are fully substituted, and a pair of vicinal quaternary carbon stereocenters, decorated on polycyclic architectures in addition to the unique ETP motif that has been recognized as acid-, base-, and redox-sensitive. A cyclo-dipeptide consisting of an essential tryptophan residue and a highly variable ancillary amino acid lies at the core of these structures; investigation of the transformations that take this simplistic core to the complex alkaloids lies at the heart of our research program.<\/jats:p>\n                  <jats:p>The dimeric epidithiodiketopiperazine alkaloids have largely resisted synthesis on account of their complexity since the 1970s when the founding members of this class, chaetocin A (Hauser, D. et al. Helv. Chim. Acta1970, 53, 1061.) and verticillin A ( Katagiri, K. et al. J. Antibiot.1970, 23, 420.), were first isolated. This was despite their potent cytotoxic and bacteriostatic activities, which were well appreciated at the time of their discovery. In the past decade, an increasing number of studies have uncovered powerful new biological processes that these molecules can uniquely effect, such as the inhibition of histone methyltransferases by chaetocin A ( Greiner, D. et al. Nat. Chem. Biol.2005, 1, 143.). In fact, the complete collection of hexahydropyrroloindoline alkaloids features a diverse range of potent biological properties including cytotoxic, antitumor, antileukemic, antiviral, antibiotic, and antinematodal activities ( Jiang, C.-S.; Guo, Y.-W.Mini-Rev. Med. Chem.2011, 11, 728.). This me\u0301lange of activities is reflective of their structural diversity.<\/jats:p>\n                  <jats:p>Under the precepts of retrobiosynthetic analysis, we have accomplished the syntheses of more than a dozen natural products, including members of the bionectin, calycanthaceous, chaetocin, gliocladin, naseseazine, and verticillin alkaloids. More importantly, these molecules have acted as venerable venues for the development of new strategies to address structural challenges including, but not limited to, C3\u2013C3\u2032 vicinal quaternary centers, heterodimeric linkages, C3\u2013Csp2 linkages, diketopiperazine oxidation, stereoselective thiolation, homologue-specific polysulfidation, and C12-hydroxyl incorporation. Synthesis of these natural products has resulted in the structural confirmation, and sometimes revision such as the case of (+)-naseseazines A and B, as well as access to many plausible biogenetically relevant intermediates and new synthetic ETP derivatives. Furthermore, our studies have paved the way for the formulation of a comprehensive SAR profile and the identification of lead compounds with in vitro subnanomolar IC50\u2019s against a broad range of cancer types.<\/jats:p>","DOI":"10.1021\/ar500454v","type":"journal-article","created":{"date-parts":[[2015,4,6]],"date-time":"2015-04-06T08:01:09Z","timestamp":1428307269000},"page":"1159-1171","source":"Crossref","is-referenced-by-count":181,"title":["Biogenetically-Inspired Total Synthesis of Epidithiodiketopiperazines\nand Related Alkaloids"],"prefix":"10.1021","volume":"48","author":[{"given":"Justin","family":"Kim","sequence":"first","affiliation":[{"name":"University of California at Berkeley , , , ,","place":["Berkeley, California, United States, 94720"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Movassaghi","sequence":"additional","affiliation":[{"name":"Massachusetts Institute of Technology , , , ,","place":["Cambridge, Massachusetts, United States, 02139"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2015,4,6]]},"reference":[{"key":"2026090301314210400_cit1","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1002\/hlca.19700530521","article-title":"Isolierung und Strukturaufkla\u0308rung\nvon Chaetocin","volume":"53","author":"Hauser","year":"1970","journal-title":"Helv. Chim. Acta"},{"key":"2026090301314210400_cit2","doi-asserted-by":"crossref","first-page":"420","DOI":"10.7164\/antibiotics.23.420","article-title":"Verticillin A, A New Antibiotic from Verticillium sp","volume":"23","author":"Katagiri","year":"1970","journal-title":"J. Antibiot."},{"key":"2026090301314210400_cit3","doi-asserted-by":"crossref","first-page":"728","DOI":"10.2174\/138955711796355276","article-title":"Epipolythiodioxopiperazines\nfrom Fungi: Chemistry and Bioactivities","volume":"11","author":"Jiang","year":"2011","journal-title":"Mini-Rev.\nMed. Chem."},{"key":"2026090301314210400_cit4","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1126\/science.1170777","article-title":"Total Synthesis of (+)-11,11\u2032-Dideoxyverticillin\nA","volume":"324","author":"Kim","year":"2009","journal-title":"Science"},{"key":"2026090301314210400_cit5","doi-asserted-by":"crossref","first-page":"3035","DOI":"10.1039\/b819925f","article-title":"Biogenetically Inspired Syntheses of Alkaloid Natural\nProducts","volume":"38","author":"Kim","year":"2009","journal-title":"Chem. Soc. Rev."},{"key":"2026090301314210400_cit6a","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1039\/c0sc00351d","article-title":"Total Synthesis of\nAll (\u2212)-Agelastatin Alkaloids","volume":"1","author":"Movassaghi","year":"2010","journal-title":"Chem.\nSci."},{"key":"2026090301314210400_cit6b","doi-asserted-by":"crossref","first-page":"10768","DOI":"10.1021\/ja204597k","article-title":"Concise Total\nSynthesis and Stereochemical Revision of all (\u2212)-Trigonoliimines","volume":"133","author":"Han","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"2026090301314210400_cit7","doi-asserted-by":"crossref","first-page":"2994","DOI":"10.1021\/ja01013a066","article-title":"A New Approach to\nSteroid Total Synthesis. A Nonenzymic Biogenetic-Like Olefinic Cyclization\nInvolving the Stereospecific Formation of Five Asymmetric Centers","volume":"90","author":"Johnson","year":"1968","journal-title":"J. Am. Chem. Soc."},{"key":"2026090301314210400_cit8","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/B978-0-12-670650-5.50015-7","article-title":"The Biosynthesis\nof Gliotoxin and Related Epipolythiodioxopiperazines","volume-title":"The Biosynthesis of Mycotoxins","author":"Kirby","year":"1980"},{"key":"2026090301314210400_cit9","first-page":"337","article-title":"The Toxicology\nof Sporidesmins and Other Epipolythiadioxopiperazines","volume-title":"Microbial Toxins","author":"Taylor","year":"1971"},{"key":"2026090301314210400_cit10","first-page":"51","article-title":"Naturally Occurring\n2,5-Dioxopiperazines and Related Compounds","volume-title":"Progress in the Chemistry of Organic Natural Products","author":"Sammes","year":"1975"},{"key":"2026090301314210400_cit11a","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1099\/mic.0.27847-0","article-title":"The Epipolythiodioxopiperazine (ETP) Class of Fungal\nToxins: Distribution, Mode of Action, Functions and Biosynthesis","volume":"151","author":"Gardiner","year":"2005","journal-title":"Microbiology"},{"key":"2026090301314210400_cit11b","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.femsle.2005.05.046","article-title":"Bioinformatic and Expression Analysis of the Putative\nGliotoxin Biosynthetic Gene Cluster of Aspergillus fumigatus","volume":"248","author":"Gardiner","year":"2005","journal-title":"FEMS Microbiol. Lett."},{"key":"2026090301314210400_cit11c","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.mycres.2007.08.017","article-title":"Biosynthetic Gene Clusters for Epipolythiodioxopiperazines\nin Filamentous Fungi","volume":"112","author":"Fox","year":"2008","journal-title":"Mycol. Res."},{"key":"2026090301314210400_cit12","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1016\/S0040-4020(01)97960-8","article-title":"Total Synthesis of Gliotoxin, Dehydrogliotoxin and Hyalodendrin","volume":"37","author":"Fukuyama","year":"1981","journal-title":"Tetrahedron"},{"key":"2026090301314210400_cit13","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1002\/cber.19711040603","article-title":"Syntheseversuche in der Reihe der 3.6-Epidithio-2.5-dioxo-piperazin-Antibiotika\nGliotoxin, Sporidesmin, Aranotin und Chaetocin, II","volume":"104","author":"Poisel","year":"1971","journal-title":"Chem. Ber."},{"key":"2026090301314210400_cit14","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.1021\/jo01301a017","article-title":"Syntheses of the Fungal Metabolites (\u00b1)-Gliovictin\nand (\u00b1)-Hyalodendrin","volume":"45","author":"Williams","year":"1980","journal-title":"J. Org. Chem."},{"key":"2026090301314210400_cit15","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1126\/science.1172081","article-title":"Total Chemical Synthesis Peers into\nthe Biosynthetic Black Box","volume":"324","author":"Miller","year":"2009","journal-title":"Science"},{"key":"2026090301314210400_cit16","doi-asserted-by":"crossref","first-page":"3725","DOI":"10.1002\/anie.200700705","article-title":"Concise Total Synthesis\nof (\u2212)-Calycanthine, (+)-Chimonanthine, and (+)-Folicanthine","volume":"46","author":"Movassaghi","year":"2007","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090301314210400_cit17","first-page":"76","article-title":"Calycanthine: The Structure of the\nAlkaloid and Its Degradation Product, Calycanine","author":"Woodward","year":"1960","journal-title":"Proc. Chem. Soc., London"},{"key":"2026090301314210400_cit18","first-page":"783","article-title":"Reactions with Nitrosodisulfonate.\nIV. Calycanthine and Calycanthidine","author":"Robinson","year":"1954","journal-title":"Chem. Ind."},{"key":"2026090301314210400_cit19","first-page":"313","article-title":"New Strategies for the Synthesis of Hexahydropyrroloindole\nAlkaloids Inspired by Biosynthetic Hypotheses","author":"Schmidt","year":"2008","journal-title":"Synlett"},{"key":"2026090301314210400_cit20","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1002\/anie.200704960","article-title":"Concise\nTotal Synthesis of (+)-WIN 64821 and (\u2212)-Ditryptophenaline","volume":"47","author":"Movassaghi","year":"2008","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090301314210400_cit21","doi-asserted-by":"crossref","first-page":"13002","DOI":"10.1021\/ja2057852","article-title":"Directed Heterodimerization: Stereocontrolled\nAssembly via Solvent-Caged Unsymmetrical Diazene Fragmentation","volume":"133","author":"Movassaghi","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"2026090301314210400_cit22","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1039\/C3SC52451E","article-title":"Application of Diazene-Directed Fragment Assembly to\nthe Total Synthesis and Stereochemical Assignment of (+)-Desmethyl-meso-chimonanthine\nand Related Heterodimeric Alkaloids","volume":"5","author":"Lathrop","year":"2014","journal-title":"Chem. Sci."},{"key":"2026090301314210400_cit23","doi-asserted-by":"crossref","first-page":"389","DOI":"10.2533\/chimia.2012.389","article-title":"Radical Mediated\nDimerization and Oxidation Reactions for the Synthesis of Complex\nAlkaloids","volume":"66","author":"Lathrop","year":"2012","journal-title":"Chimia"},{"key":"2026090301314210400_cit24","doi-asserted-by":"crossref","first-page":"3862","DOI":"10.1021\/ol901466r","article-title":"Naseseazines A and B: A New Dimeric\nDiketopiperazine Framework from a Marine-Derived Actinomycete, Streptomyces sp","volume":"11","author":"Raju","year":"2009","journal-title":"Org. Lett."},{"key":"2026090301314210400_cit25","doi-asserted-by":"crossref","first-page":"14940","DOI":"10.1021\/ja206743v","article-title":"Concise Total\nSynthesis and Stereochemical Revision of (+)-Naseseazines A and B:\nRegioselective Arylative Dimerization of Diketopiperazine Alkaloids","volume":"133","author":"Kim","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"2026090301314210400_cit27","doi-asserted-by":"crossref","first-page":"15438","DOI":"10.1021\/ja0767480","article-title":"Organocatalytic\nVinyl and Friedel\u2013Crafts Alkylations with Trifluoroborate Salts","volume":"129","author":"Lee","year":"2007","journal-title":"J. Am. Chem. Soc."},{"key":"2026090301314210400_cit28","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1021\/ar050199q","article-title":"Organotrifluoroborates: Protected Boronic Acids That Expand the Versatility\nof the Suzuki Coupling Reaction","volume":"40","author":"Molander","year":"2007","journal-title":"Acc. Chem.\nRes."},{"key":"2026090301314210400_cit29","doi-asserted-by":"crossref","first-page":"3020","DOI":"10.1021\/jo00115a016","article-title":"Conversion of Arylboronic Acids into Potassium Aryltrifluoroborates:\nConvenient Precursors of Arylboron Difluoride Lewis Acids","volume":"60","author":"Vedejs","year":"1995","journal-title":"J. Org. Chem."},{"key":"2026090301314210400_cit30","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.1039\/c2sc20270k","article-title":"Concise Total Synthesis of (+)-Gliocladins B and C","volume":"3","author":"Boyer","year":"2012","journal-title":"Chem. Sci."},{"key":"2026090301314210400_cit31","doi-asserted-by":"crossref","first-page":"3191","DOI":"10.1039\/c3sc51150b","article-title":"Concise Total Synthesis of (+)-Bionectins\nA and C","volume":"4","author":"Coste","year":"2013","journal-title":"Chem. Sci."},{"key":"2026090301314210400_cit32","doi-asserted-by":"crossref","first-page":"1880","DOI":"10.1021\/jo01298a023","article-title":"\u03b1-Functionalized Amino Acid\nDerivatives. A Synthetic Approach of Possible Biogenetic Importance","volume":"45","author":"Herscheid","year":"1980","journal-title":"J. Org. Chem."},{"key":"2026090301314210400_cit33","doi-asserted-by":"crossref","first-page":"14376","DOI":"10.1021\/ja106869s","article-title":"General Approach\nto Epipolythiodiketopiperazine Alkaloids: Total Synthesis of (+)-Chaetocins\nA and C and (+)-12,12\u2032-Dideoxychetracin A","volume":"132","author":"Kim","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"2026090301314210400_cit34a","doi-asserted-by":"crossref","first-page":"12322","DOI":"10.1021\/ja201311d","article-title":"A Dedicated Glutathione S-Transferase\nMediates Carbon-Sulfur Bond Formation in Gliotoxin Biosynthesis","volume":"133","author":"Scharf","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"2026090301314210400_cit34b","doi-asserted-by":"crossref","first-page":"11674","DOI":"10.1021\/ja5033106","article-title":"Opposed Effects\nof Enzymatic Gliotoxin N- and S-Methylations","volume":"136","author":"Scharf","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"2026090301314210400_cit35","doi-asserted-by":"crossref","first-page":"5390","DOI":"10.1021\/ja00354a034","article-title":"Alkylation\nof Amino Acids without Loss of the Optical Activity: Preparation of\n\u03b1-Substituted Proline Derivatives. A Case of Self-Reproduction\nof Chirality","volume":"105","author":"Seebach","year":"1983","journal-title":"J. Am. Chem. Soc."},{"key":"2026090301314210400_cit36","doi-asserted-by":"crossref","first-page":"4078","DOI":"10.1021\/ja101280p","article-title":"Total Synthesis of (+)-Chaetocin and Its Analogues:\nTheir Histone Methyltransferase G9a Inhibitory Activity","volume":"132","author":"Iwasa","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"2026090301314210400_cit37","doi-asserted-by":"crossref","first-page":"10064","DOI":"10.1002\/anie.201205041","article-title":"Epidithiol Formation\nby an Unprecedented Twin Carbon-Sulfur Lyase in the Gliotoxin Pathway","volume":"51","author":"Scharf","year":"2012","journal-title":"Angew. Chem., Int. Ed."},{"key":"2026090301314210400_cit38","doi-asserted-by":"crossref","first-page":"11092","DOI":"10.1002\/anie.201305059","article-title":"Epidithiodiketopiperazine\nBiosynthesis: A Four-Enzyme Cascade Converts Glutathione Conjugates\ninto Transannular Disulfide Bridges","volume":"52","author":"Scharf","year":"2013","journal-title":"Angew.\nChem., Int. Ed."},{"key":"2026090301314210400_cit39","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1016\/j.chembiol.2010.12.022","article-title":"The Role of Glutathione S-Transferase GliG in Gliotoxin Biosynthesis\nin Aspergillus fumigatus","volume":"18","author":"Davis","year":"2011","journal-title":"Chem.\nBiol."},{"key":"2026090301314210400_cit40","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1039\/c3sc50174d","article-title":"Synthesis and Anticancer Activity\nof Epipolythiodiketopiperazine Alkaloids","volume":"4","author":"Boyer","year":"2013","journal-title":"Chem.\nSci."}],"container-title":["Accounts of Chemical Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/ar500454v","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/achre4\/article-pdf\/48\/4\/1159\/16228446\/ar500454v.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/achre4\/article-pdf\/48\/4\/1159\/16228446\/ar500454v.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:31:52Z","timestamp":1788413512000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/achre4\/article\/48\/4\/1159\/1518505\/Biogenetically-Inspired-Total-Synthesis-of"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,4,6]]},"references-count":43,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2015,4,6]]},"published-print":{"date-parts":[[2015,4,21]]}},"URL":"https:\/\/doi.org\/10.1021\/ar500454v","relation":{},"ISSN":["0001-4842","1520-4898"],"issn-type":[{"value":"0001-4842","type":"print"},{"value":"1520-4898","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,4,6]]}}}