title: Design, Synthesis, and Evaluation of Irciniastatin Analogues: Simplification of the Tetrahydropyran Core and the C(11) Substituents.
abstract: The design, synthesis, and biological evaluation of irciniastatin A (1) analogues, achieved by removal of three synthetically challenging structural units, as well as by functional group manipulation of the C(11) substituent of both irciniastatins A and B (1 and 2), has been achieved. To this end, we first designed a convergent synthetic route toward the diminutive analogue (+)-C(8)-desmethoxy-C(11)-deoxy-C(12)-didesmethylirciniastatin (6). Key transformations include an acid-catalyzed 6-exo-tet pyran cyclization, a chiral Lewis acid mediated aldol reaction, and a facile amide union. The absolute configuration of 6 was confirmed via spectroscopic analysis (CD spectrum, HSQC, COSY, and ROESY NMR experiments). Structure-activity relationship (SAR) studies of 6 demonstrate that the absence of the three native structural units permits access to analogues possessing cytotoxic activity in the nanomolar range. Second, manipulation of the C(11) position, employing late-stage synthetic intermediates from our irciniastatin syntheses, provides an additional five analogues (7-11). Biological evaluation of these analogues indicates a high functional group tolerance at position C(11).
authors.affiliation: Department of Chemistry, Laboratory for Research on the Structure of Matter and Monell Chemical Senses Center, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Chemistry, Laboratory for Research on the Structure of Matter and Monell Chemical Senses Center, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Chihui
authors.initials: C
authors.lastname: An
authors.affiliation: Eisai Inc. , 4 Corporate Drive, Andover, Massachusetts 01810, United States.
authors.forename: Karen
authors.initials: K
authors.lastname: TenDyke
authors.affiliation: Eisai Inc. , 4 Corporate Drive, Andover, Massachusetts 01810, United States.
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Eisai Inc. , 4 Corporate Drive, Andover, Massachusetts 01810, United States.
authors.forename: Young Yongchun
authors.initials: YY
authors.lastname: Shen
authors.affiliation: Department of Chemistry, Laboratory for Research on the Structure of Matter and Monell Chemical Senses Center, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Adam T
authors.initials: AT
authors.lastname: Hoye
authors.affiliation: Department of Chemistry, Laboratory for Research on the Structure of Matter and Monell Chemical Senses Center, University of Pennsylvania , Philadelphia, Pennsylvania 19104, United States.
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
mesh_terms: D001686:Biological Phenomena; D002384:Catalysis; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry*; D015394:Molecular Structure; D011714:Pyrans / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D003374:Coumarins; D011714:Pyrans; C483487:irciniastatin B; C498383:psymberin