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Biomedical subjects

Sanjay Dutta

Publications and source records attributed to Sanjay Dutta.

3 recordsLinked to original sources
PubMed2005

DNA damage by fasicularin.

Fasicularin is a structurally novel thiocyanate-containing alkaloid isolated from the ascidian Nephteis fasicularis. Early biological experiments suggested that this compound's cytotoxic properties may stem from its ability to damage cellular DNA. Sequence gel analysis reveals that treatment of a 5'-32P-labeled DNA duplex with fasicularin in pH 7.0 buffer causes strand cleavage selectively at guanine residues. Further experiments indicate that production of these base-labile lesions in DNA involves alkylation of guanine residues by a fasicularin-derived aziridinium ion. This work reveals fasicularin as the first natural product found to generate a DNA-alkylating aziridinium ion via a mechanism analogous to the clinically used anticancer drugs mechlorethamine, melphalan, and chlorambucil.

Base Sequence↗
PubMed2004

Chemical properties of the leinamycin-guanine adduct in DNA.

The reaction of the antitumor agent leinamycin with thiols converts this natural product into an episulfonium ion that alkylates the N7-position of guanine residues in double-stranded DNA. It is reported here that depurination of this adduct is unusually facile, occurring with a half-life of about 3.5 h at pH 7 and 37 degrees C in duplex DNA. This is one of the most rapid depurination reactions ever observed for an N7-alkylguanine residue. The rate constant for the depurination reaction was measured at several temperatures, and the activation parameters were calculated from the data. The energy of activation (E(a)) for this reaction is 24.6 kcal/mol, and the Arrhenius A value is 1.2 x 10(13) s(-1). These values correspond to a DeltaH(++) = 24.0 kcal/mol and DeltaS(++) = -0.78 eu and are consistent with the expected unimolecular (D(N) + A(N)) mechanism for the depurination reaction. Changes in ionic strength (0-500 mM NaCl) or pH (3-8) do not significantly alter the rate of depurination, and the base excision repair protein Aag, which removes a variety of N7-alkylguanine residues from duplex DNA, does not excise the leinamycin-guanine adduct. Possible biological implications of this rapid depurination process are considered. Finally, during the course of these studies, the release of hydrolyzed leinamycin (4; Scheme 1) from leinamycin-modified DNA was observed. This result suggests that leinamycin may be a reversible DNA alkylating agent.

Animals↗