Intercalators are the most important group of compounds that interact reversibly with the DNA double helix. Some of them are valuable drugs currently used for the treatment of ovarian and breast cancers and acute leukemias, while many others are in different phases of clinical trials. Intercalating agents share common structural features such as the presence of planar polyaromatic systems which bind by insertion between DNA base-pairs, with a marked preference for 5'-pyrimidine-purine-3' steps. The chromophores are linked to basic chains that might also play an important role in the affinity and selectivity shown by these compounds. Bisintercalators have two potential intercalating ring systems connected by linkers which can vary in length and rigidity. Nowadays it is well accepted that the antitumor activity of intercalators is closely related to the ability of these compounds to stabilize the DNA-intercalator-topoisomerase II ternary complex. In this work we have carried out a revision of small organic molecules that bind to the DNA molecule via intercalation, and exert their antitumor activity through a proven topoisomerase II inhibition. We have tried to give a general overview of the most recent results in this area, paying special attention to compounds that are currently under clinical trials. Among those are naphthalimides, a group of compounds that has been developed in our laboratory since the 70's.
Naphthalimides are a class of compounds with high antitumor activity upon a variety of murine and human tumor cells. These compounds bind to DNA by intercalation of the chromophore and two of them, mitonafide and amonafide, were used in clinical trials. The therapeutic properties of these lead drugs were improved by designing bisintercalating agents. One of these, elinafide, showed intense in vitro and in vivo activity and is currently being used in clinical trials against solid tumors. In this paper, the history of elinafide is described.
LU 79553, a bis-naphthalimide drug highly active against human solid tumour xenografts, has been shown to bis-intercalate into DNA with a helix-unwinding angle of 37". Footprinting experiments with DNase I reveal that the drug is selective for mixed nucleotide sequences characterised by an alternating purine-pyrimidine motif, particularly those containing GpT (ApC) and TpG (CpA) steps. Derivatives bearing nitro or amino substituents on the naphthalimide chromophores bind at essentially identical sites. The footprinting profiles on tyrT DNA and on two fragments from pBS bear a remarkable resemblance to those determined for nogalamycin, an antibiotic which binds intercalatively leaving bulky carbohydrate substituents blocking both the major and minor grooves of the helix. Several lines of evidence indicate that the bis-naphthalimides recognise their preferred binding sites via the unusual expedient of intercalating from the major groove. Footprints on the complementary DNA strands sometimes appear staggered in the 5' direction. Repositioning the 2-amino group of G . C base pairs, which serves as a critical minorgroove marker, by substitution with inosine andor 2,6-diaminopurine has little effect on the distribution of binding sites for LU 79553. The bis-naphthalimides affect the guanine-specific reaction with dimethyl sulfate (which reacts with the N7 position of the base located in the major groove) but not reactions with tetrachloropalladinate or methylene blue. Photoactivation of LU 79553-DNA complexes leads to a small amount of strand scission mainly at guanine residues. These observations make a strong case for binding via the major groove of the double helix, in contrast to nearly all common intercalating drugs, which could be important in explaining the unique biological selectivity of bis-naphthalimides.
Pyrazolopyridazine 1a was identified in a high-throughput screening carried out by BASF Bioresearch Corp. (Worcester, MA) as a potent inhibitor of CDK1/cyclin B and shown to have selectivity for the CDK family. Analogues of the lead compound have been synthesized and their antitumor activities have been tested. A molecular model of the complex between the lead compound and the CDK2 ATP binding site has been built using a combination of conformational search and automated docking techniques. The stability of the resulting complex has been assessed by molecular dynamics simulations and the experimental results obtained for the synthesized analogues have been rationalized on the basis of the proposed binding mode for compound 1a. As a result of the SAR study, monofuryl 1o has been synthesized and is one of the most active compounds against CDK1 of this series.
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