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More selective, efficient, and less toxic anticancer agents are needed. We synthesized seven, new, optically pure (12a<jats:italic>S<\/jats:italic>)\u20101,3,4,12a\u2010tetrahydropyrazino[2,1\u2010<jats:italic>c<\/jats:italic>][1,4],12(2<jats:italic>H<\/jats:italic>,11<jats:italic>H<\/jats:italic>)\u2010dione derivatives and examined their cytotoxicity towards eight cancer cell lines, including urinary bladder (TCC\u2010SUP, UM\u2010UC\u20103, KU\u201019\u20109), colon (LoVo), and breast (MCF\u20107, MDA\u2010MB\u2010231) cancer representatives, as well as two leukemic cell lines (MV\u20104\u201011, CCRF\u2010CEM) and normal murine fibroblasts (Balb\/3T3) as reference cell line. Three of the seven newly\u2010obtained compounds ((12a<jats:italic>S<\/jats:italic>)\u20108\u2010bromo\u20102\u2010(3\u2010phenylbenzoyl)\u20101,3,4,12a\u2010tetrahydropyrazino[2,1\u2010<jats:italic>c<\/jats:italic>][1,4],12(2<jats:italic>H<\/jats:italic>,11<jats:italic>H<\/jats:italic>)\u2010dione, (12a<jats:italic>S<\/jats:italic>)\u20108,9\u2010dimethoxy\u20102\u2010(4\u2010phenylbenzoyl)\u20101,3,4,12a\u2010tetrahydropyrazino[2,1\u2010<jats:italic>c<\/jats:italic>][1,4],12(2<jats:italic>H<\/jats:italic>,11<jats:italic>H<\/jats:italic>)\u2010dione and (12a<jats:italic>S<\/jats:italic>)\u20108\u2010nitro\u20102\u2010(4\u2010phenylbenzoyl)\u20101,3,4,12a\u2010tetrahydropyrazino[2,1\u2010<jats:italic>c<\/jats:italic>][1,4],12(2<jats:italic>H<\/jats:italic>,11<jats:italic>H<\/jats:italic>)\u2010dione, showed enhanced activity and selectivity toward the leukemic MV\u20104\u201011\u2005cell lines when compared to our previously reported compounds, with IC<jats:sub>50<\/jats:sub> values in the range of 2.9\u20135.6\u2005\u03bcM. Additionally, (12a<jats:italic>S<\/jats:italic>)\u20109\u2010nitro\u20102\u2010(4\u2010phenylbenzoyl)\u20101,3,4,12a\u2010tetrahydropyrazino[2,1\u2010<jats:italic>c<\/jats:italic>][1,4],12(2<jats:italic>H<\/jats:italic>,11<jats:italic>H<\/jats:italic>)\u2010dione exhibited a strong cytotoxic effect against the leukemic CCRF\u2010CEM (IC<jats:sub>50<\/jats:sub>=6.1\u2005\u03bcM) and MV\u20104\u201011 (IC<jats:sub>50<\/jats:sub>=11.0\u2005\u03bcM) cell lines, a moderate cytotoxic effect toward other tumor lines (IC<jats:sub>50<\/jats:sub>=31.8\u201355.0\u2005\u03bcM) and very weak cytotoxic effect toward the Balb\/3T3 reference cell lines. Selected compounds were further evaluated for their potential to induce apoptotic cell death in MV\u20104\u201011 cells by measuring caspase\u20103 activity. We also established the crystal structure of three products and investigated the effect of 22 derivatives of 1,3,4,12a\u2010tetrahydropyrazino[2,1\u2010<jats:italic>c<\/jats:italic>][1,4],12(2<jats:italic>H<\/jats:italic>,11<jats:italic>H<\/jats:italic>)\u2010dione on the activity of the cancer\u2010associated enzyme autotaxin. All compounds proved to be weak inhibitors of autotaxin, although some (<jats:italic>R<\/jats:italic>) and (<jats:italic>S<\/jats:italic>) enantiomers had <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub> values of 10\u201319\u2005\u03bcM. The obtained results showed that the tested compounds exhibited a selective antileukemic effect, which appeared not to be related directly to autotaxin. Molecular targets responsible for this effect remain to be identified. The newly obtained compounds can be used in the search for new, selective anticancer therapies.<\/jats:p>","DOI":"10.1002\/cbdv.202000733","type":"journal-article","created":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T06:42:47Z","timestamp":1606286567000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Design and in Vitro Characterization of Tricyclic Benzodiazepine Derivatives as Potent and Selective Antileukemic Agents"],"prefix":"10.1002","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5104-2564","authenticated-orcid":false,"given":"Adam","family":"Mieczkowski","sequence":"first","affiliation":[{"name":"Institute of Biochemistry and Biophysics Polish Academy of Sciences  Pawinskiego 5a 02-106 Warsaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2084-3446","authenticated-orcid":false,"given":"Tomasz","family":"Fr\u0105czyk","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Biophysics Polish Academy of Sciences  Pawinskiego 5a 02-106 Warsaw Poland"},{"name":"Medical University of Warsaw  Nowogrodzka 59 02-006 Warsaw Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8866-7149","authenticated-orcid":false,"given":"Mateusz","family":"Psurski","sequence":"additional","affiliation":[{"name":"Hirszfeld Institute of Immunology and Experimental Therapy Polish Academy of Sciences, R.  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