N,N-Bis(glycityl)amines as anti-cancer drugs.
A series of N,N-bis(glycityl)amines with promising anti-cancer activity were prepared via the reductive amination of pentoses and hexoses, and subsequently screened for their ability to selectively inhibit the growth of cancerous versus non-cancerous cells. For the first time, we show that this class of compounds possesses anti-proliferative activity, and, while the selective killing of brain cancer (LN18) cells versus matched (SVG-P12) cells was modest, several of the amines, including d-arabinitylamine 1a and d-fucitylamine 1g, exhibited low micromolar IC50 values for HL60 cells. Moreover, these two amines showed good selectivity towards HL60 cells when compared to non-cancerous HEK-293 cells. The compounds also showed low micromolar inhibition of the leukaemic cell line, THP-1. The modes of action of amines 1a and 1g were then determined using yeast chemical genetics, whereby it was established that both compounds affect similar but distinct sets of biochemical pathways. Notably purine nucleoside monophosphate biosynthesis was identified as an enriched mechanism. The rapid synthesis of the amines and their unique mode of action thus make them attractive targets for further development as anti-cancer drugs.
School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, 6140 Wellington, New Zealand.
Charlotte L
CL
Waghorne
School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, 6140 Wellington, New Zealand; Malaghan Institute of Medical Research, PO Box 7060, Wellington, New Zealand.
Hilary M
HM
Corkran
School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, 6140 Wellington, New Zealand.
Alex A
AA
Hunt-Painter
School of Biological Sciences, Victoria University of Wellington, PO Box 600, 6140 Wellington, New Zealand.
Eliatan
E
Niktab
Malaghan Institute of Medical Research, PO Box 7060, Wellington, New Zealand.
James W
JW
Baty
Malaghan Institute of Medical Research, PO Box 7060, Wellington, New Zealand.
Michael V
MV
Berridge
School of Biological Sciences, Victoria University of Wellington, PO Box 600, 6140 Wellington, New Zealand.
Andrew B
AB
Munkacsi
School of Biological Sciences, Victoria University of Wellington, PO Box 600, 6140 Wellington, New Zealand.
Melanie J
MJ
McConnell
School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, 6140 Wellington, New Zealand.
Mattie S M
MSM
Timmer
School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, 6140 Wellington, New Zealand; Malaghan Institute of Medical Research, PO Box 7060, Wellington, New Zealand. Electronic address: bridget.stocker@vuw.ac.nz.
Bridget L
BL
Stocker
D000606:Amino Sugars / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013402:Sugar Alcohols / Q000138:chemical synthesis / Q000494:pharmacology*; D012359:tRNA Methyltransferases / Q000235:genetics / Q000378:metabolism
D000606:Amino Sugars; D000970:Antineoplastic Agents; D029701:Saccharomyces cerevisiae Proteins; D013402:Sugar Alcohols; D004317:Doxorubicin; D012359:tRNA Methyltransferases; C112078:DBP7 protein, S cerevisiae; D053487:DEAD-box RNA Helicases
Amine; Anti-cancer; Carbohydrate; Chemical genetics; Synthesis