Synthesis and in vitro evaluation of 3h-pyrrolo[3,2-f]-quinolin-9-one derivatives that show potent and selective anti-leukemic activity.
A series of new substituted 7-phenyl-3H-pyrrolo[3,2-f]quinolin-9-ones were synthesized and evaluated for their antiproliferative activity. The most active derivatives showed high selectivity against human leukemia cell lines and potently inhibited their growth, with GI(50) values in the nanomolar range. The active compounds strongly blocked tubulin assembly and colchicine binding to tubulin. Their activities were equal to or greater than that of the reference compound combretastatin A-4. Flow cytometry studies showed that the two most active compounds arrested Jurkat cells in the G(2)/M cell-cycle phase in a concentration-dependent manner. This effect was associated with apoptosis, mitochondrial depolarization, generation of reactive oxygen species, activation of caspase-3, and cleavage of the enzyme poly(ADP-ribose) polymerase.
Ferlin
Maria Grazia
MG
Department of Pharmaceutical Sciences, University of Padova, Italy. mariagrazia.ferlin@unipd.it
Bortolozzi
Roberta
R
Brun
Paola
P
Castagliuolo
Ignazio
I
Hamel
Ernest
E
Basso
Giuseppe
G
Viola
Giampietro
G
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D017209:Apoptosis; D002455:Cell Division; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D016195:G2 Phase; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use
D000970:Antineoplastic Agents; D011758:Pyrroles; D011804:Quinolines; D017382:Reactive Oxygen Species; D014404:Tubulin; D050257:Tubulin Modulators; C410406:pyrroloquinoline