N-picolyl derivatives of Kemp's triamine as potential antitumor agents: a preliminary investigation.
Preorganized tripodal ligands such as the N-picolyl derivatives of cis,cis-1,3,5-triamino-cis,cis-1,3,5-trimethylcyclohexane (Kemp's triamine) were prepared as analogues to N,N',N''-tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane (tachpyr) in hopes of enhancing the rate of formation and stability of the metal complexes. A tricyclic bisaminal was formed via the reduction of the Schiff base, while the tri(picolyl) derivative was synthesized via reductive amination of pyridine carboxaldehyde. Their cytotoxicities to the HeLa cell line were evaluated and directly compared to tachpyr and N,N',N''-tris(2-pyridylmethyl)tris(2-aminoethyl)amine (trenpyr). Results indicate that N,N',N''-tris(2-pyridylmethyl)-cis,cis-1,3,5-triamino-cis,cis-1,3,5-trimethylcyclohexane (Kemp's pyr) exhibits cytotoxic activity against the HeLa cancer cell line comparable to tachpyr (IC50 approximately 8.0 microM). Both Kemp's pyr and tachpyr show higher cytotoxic activity over the aliphatic analogue of trenpyr (IC50 approximately 14 microM), suggesting that the major contributor to the activity is the ligand's ability to form a stable and tight complex and that the equatorial/axial equilibrium impacting the complex formation for the cyclohexane-based ligands is not significant.
Regino
Celeste Aida S
CA
Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, Maryland 20892, USA.
Torti
Suzy V
SV
Ma
Rong
R
Yap
Glenn P A
GP
Kreisel
Kevin A
KA
Torti
Frank M
FM
Planalp
Roy P
RP
Brechbiel
Martin W
MW
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003300:Copper; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003514:Cyclohexylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005029:Ethylenediamines / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010848:Picolinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015032:Zinc
D000970:Antineoplastic Agents; D002614:Chelating Agents; D003510:Cyclohexanes; D003514:Cyclohexylamines; D005029:Ethylenediamines; C507632:N,N',N''-tris(2-pyridylmethyl)-1,3,5-triamino-1,3,5-trimethylcyclohexane; C507631:N,N',N''-tris(2-pyridylmethyl)tris(2-aminoethyl)amine; D009942:Organometallic Compounds; D010848:Picolinic Acids; D011725:Pyridines; C114047:tachpyr; D003300:Copper; D015032:Zinc