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It has already been stressed that the majority of known drugs tend to be flat, whereas natural products tend to be more tridimensional and represent a good source of active compounds. 3D metrics have been implemented and computational descriptors are available to evaluate and prioritize compounds based on their 3D geometry. This is usually done by comparing the saturated carbon atoms in a molecule with the total number of its non\u2010hydrogen atoms (the Fsp3 value). While this aspect is clear, still there are not enough synthetic tools that support the realization of novel chemotypes that conform to these criteria. Herein we describe a diversity oriented synthesis (DOS) synthetic cascade technology that starts from two simple reagents, and generates highly enriched Fsp3 novel and diverse spiro\u2010scaffolds with pragmatic synthetic handles (points of diversity). The spiro nature of these scaffolds not only ensures high Fsp3 values but renders the compounds more rigid and therefore more effective in forming precise stereo\u2010interactions with their potential biological targets. These compounds were also profiled for their drug\u2010like properties and as potential modulators of the NNMT enzyme.<\/jats:p>","DOI":"10.1002\/cmdc.202200394","type":"journal-article","created":{"date-parts":[[2022,10,4]],"date-time":"2022-10-04T06:36:55Z","timestamp":1664865415000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Design and Synthesis of Fsp3\u2010Enriched Spirocyclic\u2010Based Biological Screening Compound Arrays via DOS Strategies and Their NNMT Inhibition Profiling"],"prefix":"10.1002","volume":"17","author":[{"given":"Ildar R.","family":"Iusupov","sequence":"first","affiliation":[{"name":"Department of Chemistry Lomonosov Moscow State University  1\/3 Leninsky Gory Moscow 119991 Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evgeny R.","family":"Lukyanenko","sequence":"additional","affiliation":[{"name":"Department of Chemistry Lomonosov Moscow State University  1\/3 Leninsky Gory Moscow 119991 Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Altieri","sequence":"additional","affiliation":[{"name":"Department of Chemistry Lomonosov Moscow State University  1\/3 Leninsky Gory Moscow 119991 Russia"},{"name":"EDASA Scientific Srls  Via Stingi, 3 66050 San Salvo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8467-9721","authenticated-orcid":false,"given":"Alexander V.","family":"Kurkin","sequence":"additional","affiliation":[{"name":"Department of Chemistry Lomonosov Moscow State University  1\/3 Leninsky Gory Moscow 119991 Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,10,27]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-409X(96)00423-1"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm049717d"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2019.10.014"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm9602928"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2018.10.016"},{"key":"e_1_2_9_6_1","first-page":"277","volume":"19","author":"Paricharak S.","year":"2018","journal-title":"Briefings Bioinf."},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2021.04.019"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd1035"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm901241e"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-020-00114-z"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/chir.20930"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-37253-8"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1063\/5.0020997"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2016.00083"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2014.06.081"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.2147\/JPR.S278279"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.07-095398"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.115.228221"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm801517j"},{"key":"e_1_2_9_20_1","unstructured":"\u00a0"},{"key":"e_1_2_9_21_2","first-page":"29","author":"Krishna S.","year":"2008","journal-title":"Trends Pharmacol. 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