Synthesis and biological evaluation of analogs of the marine alkaloids granulatimide and isogranulatimide.
A series of pyrrolic analogs and two series of regioisomeric pyrazolic analogs of the marine alkaloids granulatimide and isogranulatimide were prepared. The synthesis of the two first ones was based on the condensation reaction of diversely 5-substituted 3-bromoindoles with pyrrole or pyrazole followed by addition of the intermediates on maleimide or dibromomaleimide, respectively, the so-obtained acyclic adducts being finally photocyclized to the desired analogs. Compounds of the last series were obtained by reacting different 5-substituted-indole-3-glyoxylates with N-Boc-pyrazole-3-acetamide and subsequent photochemical cyclization of the adducts. All the compounds were evaluated for their in vitro growth inhibitory properties toward eight cancer cell lines. Several compounds were also assayed for their ability to abrogate the G2-cell cycle checkpoint or to inhibit a panel of Ser/Thr kinases. Lastly, computer-assisted phase-contrast microscopy (quantitative videomicroscopy) revealed that the three most potent compounds (4a, 9a, 9e), with IC(50) growth inhibitory concentrations ranging between 10 and 20 μM, displayed cytostatic, not cytotoxic, anticancer effects.
Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt Biologique, Université Paul Sabatier, UMR CNRS 5068, 118 route de Narbonne, 31062 Toulouse Cédex 9, France.
Sébastien
S
Deslandes
Delphine
D
Lamoral-Theys
Céline
C
Frongia
Stefan
S
Chassaing
Céline
C
Bruyère
Olivier
O
Lozach
Laurent
L
Meijer
Bernard
B
Ducommun
Robert
R
Kiss
Evelyne
E
Delfourne
D000470:Alkaloids / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D059001:Aquatic Organisms / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology
D000470:Alkaloids; D000970:Antineoplastic Agents; D007093:Imidazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; C433587:granulatimide; C116644:isogranulatimide