The anti-cancer, anti-inflammatory and tuberculostatic activities of a series of 6,7-substituted-5,8-quinolinequinones.
A variety of 6,7-substituted-5,8-quinolinequinones were synthesised and assessed for their anti-tumour and anti-inflammatory activities, and their ability to inhibit the growth of Mycobacterium bovis BCG. In particular, the introduction of a sulfur group at the 7-position of the quinolinequinone led to the discovery of two compounds, 6-methylamino-7-methylsulfanyl-5,8-quinolinequinone (10a) and 6-amino-7-methylsulfonyl-5,8-quinolinequinone (12), that exhibited selectivity for leukemic cells over T-cells, a highly desirable property for an anti-cancer drug. A number of anti-inflammatory (AI) compounds were also identified, with 6,7-bis-methylsulfanyl-5,8-quinolinequinone (18a) exhibiting the highest AI activity (0.11 microM), while 6,7-dichloro-5,8-quinolinequinone (7a), 6,7-dichloro-2-methyl-5,8-quinolinequinone (7b), and 6,7-bis-phenylsulfanyl-quinoline-5,8-diol (19) also exhibited good AI activity and specificity. Several quinolinequinone TB-drug candidates were identified. Of these, 6-amino-7-chloro-5,8-quinolinequinone (11) and 6-amino-7-methanesulfinyl-5,8-quinolinequinone (14), exhibited low MICs (1.56-3.13 microg/mL) for the 100% growth inhibition of M. Bovis BCG. Some general trends pertaining to the functional group substitution of the quinolinequinone core and biological activity were also identified.
Mulchin
Benjamin J
BJ
Malaghan Institute of Medical Research, PO Box 7060, Wellington, New Zealand.
Newton
Christopher G
CG
Baty
James W
JW
Grasso
Carole H
CH
Martin
William John
WJ
Walton
Michaela C
MC
Dangerfield
Emma M
EM
Plunkett
Catherine H
CH
Berridge
Michael V
MV
Harper
Jacquie L
JL
Timmer
Mattie S M
MS
Stocker
Bridget L
BL
D000588:Amines / Q000737:chemistry; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002713:Chlorine / Q000737:chemistry; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009163:Mycobacterium bovis / Q000187:drug effects*; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011809:Quinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013455:Sulfur / Q000737:chemistry
D000588:Amines; D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D000995:Antitubercular Agents; D015363:Quinolones; D011809:Quinones; C031241:6-(cyclooctylamino)-5,8-quinolinequinone; D002713:Chlorine; D013455:Sulfur