Novel naphthoquinonyl derivatives: Potential structural components for the synthesis of cytotoxic peptides

Abstract

Syntheses and physicochemical properties are described of several novel naphthoquinonyl amino acid derivatives, which are potential components in cytotoxic peptide conjugates. These compounds include N E-and N~-naphthoquinonyl derivatives of lysine as well as N-naphthoquinonyl-carboxylic derivatives. The former class of compounds can be employed as building blocks in a stepwise peptide synthesis, whereas the latter two are adequate for postpeptide chain-assembly modifications. The ability of the naphthoquinonyl derivatives to produce semiquinone radicals and hydroxyl radicals ('OH), using chemical (i.e. NaBH4) and enzymatic (i.e. NADPH-cytochrome P-450 reductase) routes, respectively, was evaluated employing electron spin resonance spectroscopy.

Synthesis, electrochemical and spectral properties of some ω-N-quinonyl amino acids

“…This behavior, which is similar to that found for the 1,4-naphthoquinonyl amino acids series, suggests that the glycine derivative forms also an unstable semiquinone anion-radical, which undergoes NH-CH 2 or CH 2 -CO 2 H bond cleavage, thus forming the appropriate 2-amino-1,4-naphthoquinone. EPR studies of semiquinone anion radicals of different quinonyl amino acids (Bittner et al, 2000;Rahimipour et al, 1996) proved that while the unpaired electron is equally distributed on the naphthalenic ring, its density is mainly localized on the nitrogen atom. The unstable semiquinone radical leads to spontaneous decomposition of the semiquinone via the side chain cleavage.…”

Cytotoxic peptides: Naphthoquinonyl derivatives of luteinizing hormone-releasing hormone

“…Since the efficiency of quinones in the inhibition of cancer cell growth is believed to be related to their capability to produce ROS as mentioned above, the ability of the various cytotoxic quinonic analogs of suits confirm that less than 5% of [D-Lys6]-LH-RH-Q was degraded by the generation of ROS, similarly to the cytotoxic moiety alone [24]. It should be noted that the enzymatic reduction was performed while employing a much larger excess of enzyme and a substantially extended reaction time as compared to the general conditions outlined in the Materials and methods section.…”

Derivatives of aminoquinones with N-protected amino acids

“…Even though quinonylamino acids can also be prepared from the corresponding quinones and free amino acids [10,11], this new synthetic approach appears to be the most promising, as aminoquinones can serve as substrates for anchoring not only amino acids but peptides of various length as well. The coupling of some di-and tripeptides with these two aminoquinones is in progress and will be reported soon.…”

“…sis of quinonyl-amino acids from 1,4 naphthoquinone or 2,3 dichloro-l,4-naphthoquinone with free or protected heterocyclic amino acids has been recently reported [10,11]. Heterocyclic amino acids play important functional and structural roles in many bioactive peptides.…”