We here wish to disclose a novel nucleic acid analogue which displays exceptional structural simplicity and atom economy while supporting stable duplex formation. The discovered glycol nucleic acid (GNA) uses the canonical Watson-Crick base pairing scheme combined with an acyclic three-carbon propylene glycol phosphodiester backbone (Figure 1).Groundbreaking studies of the Eschenmoser group on the chemical etiology of nucleic acid structure have demonstrated that Watson-Crick base pairing can be supported by sugars in the backbone that differ from RNA or DNA. 1-3 Most surprisingly, a nucleic acid derived from a tetrose sugar (TNA) was found to be capable of antiparallel duplex formation and crosspairing with DNA and RNA (Figure 1). 4 Our laboratory is interested in structurally simplified nucleic acid backbones in order to improve synthetic accessibility of artificial duplexes. Inspired by Eschenmoser's TNA structure, we envisioned that acyclic glycol nucleosides could be synthesized just by regioselective and stereospecific nucleophilic ring opening of a "spring-loaded" epoxide. 5,6 Accordingly, commercially available (R)-(+)-and (S)-(-)-glycidol were tritylated to 1 following a standard protocol and successfully ring opened with the unprotected nucleobases thymine and adenine in the presence of substoichiometric amounts of NaH, yielding 2 and 3, respectively ( Figure 2). 7 The thymine derivative was directly transformed into the final phosphoramidite 4, whereas the adenine derivative was first benzoylated at the exocyclic amino group, followed by the formation of the final phosphoramidite 5 for the automated solid-phase oligonucleotide synthesis. With 4 and 5 in hand, we synthesized seven 18mer oligonucleotides consisting entirely out of either enantiomer of the acyclic glycol nucleotides (Table 1) (Figure 1). . (R)-(+)-glycidol yields (S)-GNA, and (S)-(-)-glycidol yields (R)-GNAFirst, we investigated duplex formation of GNA with temperature-dependent UV spectroscopy at 260 nm. Figure 3 displays the results with (S)-GNA. Mixtures (1:1) of two complementary strands, 6:7 and 8:9, yield characteristic sigmoidal melting curves with melting points (T M ) of 63°C each, thus indicating cooperative melting of GNA duplexes. No sigmoidal melting and weaker hyperchromicities were observed with the single strands alone (Figure 3a,b) or with two strands 8:10 that are complementary in a parallel fashion (Figure 3c), indicating the requirement for antiparallel duplex formation of GNA. To reassure that the duplex relies on proper Watson-Crick base pairing, we also investigated the UV melting behavior of an 18mer duplex 8:11 which contains one T:T mismatch. The stability of this duplex decreases significantly, yielding a T M of only 55°C for the single mismatched duplex. Furthermore, a duplex 8:12 with two mismatches (one T:T and one A:A) is further destabilized with a T M of only 44°C ( Figure 3c). Identical results were obtained with the enantiomeric (R)-GNA strands.For subsequent analysis, we investigated duplex forma...

The antitumor and DNA-binding properties of a group of oligomeric platinum(II) and platinum(IV) complexes are described. The compounds, having the stoichiometry [cis-PtII(X)2(mu-OH)]2(NO3)2, where X is NH3, NH2CH2CH3, and NH2CH(CH3)2, were found to be inactive or only weakly active against L-1210 leukemia. In vitro studies involving PM2-DNA show that these compounds bind to and unwind closed circular DNA in a manner similar to cis-PtII-(NH3)2Cl2. The Pt(IV) complexes produced by hydrogen peroxide oxidation of the Pt(II) dimers are inactive as antitumor agents and are incapable of unwinding PM2-DNA. The cyclotrimer [cis-PtII(RR-DACH)(mu-OH)]3(NO3)3, where RR-DACH is (R,R)-1,2 diaminocyclohexane, exhibits potent antitumor activity against L-1210 leukemia and modest activities with B-16 and M5076 tumor lines. This compound platinates DNA, causing DNA unwinding and mobility shifts.