{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T06:32:30Z","timestamp":1790058750997,"version":"4.0.1"},"reference-count":133,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2015,1,29]],"date-time":"2015-01-29T00:00:00Z","timestamp":1422489600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2015,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The natural products rhizopodin and bistramide belong to an elite class of highly potent actin binding agents. They show powerful antiproliferative activities against a range of tumor cell lines, with IC<jats:sub>50<\/jats:sub> values in the low\u2010nanomolar range. At the molecular level they disrupt the actin cytoskeleton by binding specifically to a few critical sites of G\u2010actin, resulting in actin filament stabilization. The important biological properties of rhizopodin and bistramide, coupled with their unique and intriguing molecular architectures, render them attractive compounds for further development. However, this is severely hampered by the structural complexity of these metabolites. We initiated an interdisciplinary approach at the interface between molecular modeling, organic synthesis, and chemical biology to support further biological applications. We also wanted to expand structure\u2013activity relationship studies with the goal of accessing simplified analogues with potent biological properties. We report computational analyses of actin\u2013inhibitor interactions involving molecular docking, validated on known actin binding ligands, that show a close match between the crystal and modeled structures. Based on these results, the ligand shape was simplified, and more readily accessible rhizopodin\u2013bistramide mimetics were designed. A flexible and modular strategy was applied for the synthesis of these compounds, enabling diverse access to dramatically simplified rhizopodin\u2013bistramide hybrids. This novel analogue class was analyzed for its antiproliferative and actin binding properties.<\/jats:p>","DOI":"10.1002\/cmdc.201402508","type":"journal-article","created":{"date-parts":[[2015,1,29]],"date-time":"2015-01-29T16:59:08Z","timestamp":1422550748000},"page":"470-489","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Design, Synthesis, and Biological Evaluation of Simplified Side Chain Hybrids of the Potent Actin Binding Polyketides Rhizopodin and Bistramide"],"prefix":"10.1002","volume":"10","author":[{"given":"Daniel","family":"Herkommer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Dreisigacker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Galina","family":"Sergeev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florenz","family":"Sasse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Gohlke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Menche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,1,29]]},"reference":[{"key":"e_1_2_6_1_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biophys.29.1.545"},{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)51454-X"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(98)80095-1"},{"key":"e_1_2_6_4_2","first-page":"511","volume":"5","author":"Giganti A.","year":"2003","journal-title":"Prog. Cell Cycle Res."},{"key":"e_1_2_6_5_2","unstructured":"\u00a0"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/35040061"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(00)00180-0"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0029(19991001)47:1<18::AID-JEMT3>3.0.CO;2-E"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1059700"},{"key":"e_1_2_6_10_2","unstructured":"For reviews see:"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200290057"},{"key":"e_1_2_6_11_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.200290059"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-006-6157-9"},{"key":"e_1_2_6_13_2","unstructured":"Other natural products such as the latrunculins selectively address the ATP binding pocket between domains 2 and 4 leading to significant conformational changes within both these domains. As a result the actin monomers can no longer interact with the existing filament or other monomers and therefore polymerization is effectively suppressed:"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.6681676"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(87)81513-2"},{"key":"e_1_2_6_16_2","unstructured":"\u00a0"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2233339100"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsb1006"},{"key":"e_1_2_6_19_2","unstructured":"\u00a0"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00264a052"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00264a053"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo00256a021"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo00267a024"},{"key":"e_1_2_6_24_2","unstructured":"\u00a0"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1002\/hlca.19890720207"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4020(01)96271-4"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4020(01)85019-5"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/1099-0690(200101)2001:1<39::AID-EJOC39>3.0.CO;2-9"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0502089102"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2008.01.010"},{"key":"e_1_2_6_31_2","unstructured":"\u00a0"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)61925-1"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)61853-1"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.1248\/cpb.38.2409"},{"key":"e_1_2_6_35_2","doi-asserted-by":"publisher","DOI":"10.1021\/jo00011a033"},{"key":"e_1_2_6_36_2","doi-asserted-by":"publisher","DOI":"10.1039\/p19910003185"},{"key":"e_1_2_6_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4039(00)93962-5"},{"key":"e_1_2_6_38_2","doi-asserted-by":"publisher","DOI":"10.1248\/cpb.42.19"},{"key":"e_1_2_6_39_2","unstructured":"\u00a0"},{"key":"e_1_2_6_40_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00076a082"},{"key":"e_1_2_6_41_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja00095a071"},{"key":"e_1_2_6_42_2","unstructured":"\u00a0"},{"key":"e_1_2_6_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4020(01)85836-1"},{"key":"e_1_2_6_44_2","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/BF00685536","volume":"28","author":"Roussakis C.","year":"1991","journal-title":"Cancer Chemother. 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Gelsolin was aligned from the corresponding co\u2010crystal with actin (PDB ID: 1H1V). The position of bistramide in panels\u2005a) and b) was obtained by alignment from co\u2010crystal PDB ID: 1FXU and the position of kabiramide\u2005C was obtained by alignment from structure PDB ID: 1QZ5."},{"key":"e_1_2_6_85_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B"},{"key":"e_1_2_6_86_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1999.3371"},{"key":"e_1_2_6_87_2","unstructured":"The results for the smaller search areas (75 and 60 grid points in each dimension) are depicted in the Supporting Information. The docking convergence (number of structures in the highest populated cluster) are also summarized there."},{"key":"e_1_2_6_88_2","unstructured":"Residue F375 is located at the end of the protein sequence and not resolved in all crystal structures."},{"key":"e_1_2_6_89_2","unstructured":"\u00a0"},{"key":"e_1_2_6_90_2","doi-asserted-by":"publisher","DOI":"10.1080\/00397911.2010.536293"},{"key":"e_1_2_6_91_2","unstructured":"Enantiomeric excess was determined by HPLC analysis of a corresponding urea derivative according to:L.Merritt J. S.Ward(Eli Lilly Co.) Int. PCT Pub. No. WO1998054179 1998;"},{"key":"e_1_2_6_91_3","first-page":"38385","volume":"130","year":"1998","journal-title":"Chem. 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BHK (GBF hamster): 30\u2005ng\u2009mL\u22121; L929 (mouse): 15\u2005ng\u2009mL\u22121."},{"key":"e_1_2_6_121_2","unstructured":"Compound53was prepared by coupling a diastereomeric mixture of21\u2009a(derived from reaction of34with an older partially racemized batch of Roche aldehyde35) with 1.5\u2005equiv (2S 3R)\u20104\u2010((tert\u2010butoxycarbonyl)(methyl)amino)\u20103\u2010hydroxy\u20102\u2010methylbutanoic acid (see synthesis of17) using DEPBT (3.0\u2005equiv) Et3N (7.5\u2005equiv) and Na2CO3(5.0\u2005equiv) in 51\u2009% yield."},{"key":"e_1_2_6_122_2","unstructured":"Compound54was prepared by coupling a diastereomeric mixture of21\u2009a(derived from reaction of34with an older partially racemized batch of Roche aldehyde35) with19(1.4\u2005equiv) using DEPBT (3.0\u2005equiv) Et3N (7.5\u2005equiv) and Na2CO3(5.0\u2005equiv) in 68\u2009% yield."},{"key":"e_1_2_6_123_2","unstructured":"In agreement with these data very little or no effects on the actin polymerization were visible in in vitro assays (actin polymerization biochem kit muscle actin with rhizopodin as control) at concentrations up to 1000\u2005\u03bcM; see the Supporting Information for details."},{"key":"e_1_2_6_124_2","unstructured":"Macromodel ver.\u20059.7 Schr\u00f6dinger LLC New York NY (USA) 2009."},{"key":"e_1_2_6_125_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja9621760"},{"key":"e_1_2_6_126_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm025507u"},{"key":"e_1_2_6_127_2","unstructured":"Extra signals due to amide conformers marked with an asterisk: a)\u2005conformer ratio=1:1; b)\u2005conformer ratio=6:4; c)\u2005conformer ratio=65:35; d)\u2005conformer ratio=8:2; e)\u2005conformer ratio=9:1; f) conformer ratio=75:25."}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcmdc.201402508","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.201402508","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T12:09:47Z","timestamp":1760270987000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.201402508"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,1,29]]},"references-count":133,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2015,3]]}},"alternative-id":["10.1002\/cmdc.201402508"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.201402508","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,1,29]]},"assertion":[{"value":"2014-11-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-01-29","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}