Synthesis and binding properties to DNA and to opioid receptors of enkephalin-ellipticinium conjugates.
In order to specifically direct cytotoxic agents against tumor cells bearing delta opioid receptors, the DNA intercalating agents ellipticine and 9-OH-ellipticine were coupled by quaternarization of the pyridine nitrogen to an enkephalin modified pentapeptide through a short chemical linker. The ellipticine ring of these conjugates was shown to intercalate into DNA, with DNA affinity constants close to those of the non-conjugated ellipticines. Despite the addition of a polycyclic ring to the C-terminal amino acid, the D-Ala2-D-Leu5-enkephalin-ellipticine conjugates bind to the opioid receptor from rat brain and NG 108-15 cells with an affinity constant close to 10(8) M-1. Other derivatives were synthesized as a control using a tripeptide which does not bind to the opioid receptor.
Rigaudy
P
P
Department of Organic Chemistry, U 266 INSERM and U 498 CNRS, UER of the Pharmaceutical and Biological Sciences, Villejuif, France.
Garbay-Jaureguiberry
C
C
Jacquemin-Sablon
A
A
Le Pecq
J B
JB
Roques
B P
BP
D000470:Alkaloids / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004247:DNA / Q000378:metabolism*; D004611:Ellipticines / Q000378:metabolism*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000378:metabolism; D016308:Enkephalin, Leucine-2-Alanine; D004745:Enkephalins / Q000378:metabolism*; D006801:Humans; D009842:Oligopeptides / Q000378:metabolism; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism*
D000470:Alkaloids; D004611:Ellipticines; D004745:Enkephalins; D009842:Oligopeptides; D011957:Receptors, Opioid; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C034192:ellipticine; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; C037653:deltakephalin; D004247:DNA