Current medicinal chemistry. Anti-cancer agents最新文献

Antitumor agents targeting DNA and DNA-associated processes are widely used in the treatment of human cancers and produce significant increases in the survival of patients. DNA topoisomerases remain the most significant target of these cytotoxic drugs and constitute a growing family of nuclear enzymes that regulate DNA topology during DNA replication and recombination, DNA transcription, chromosome condensation-decondensation and segregation. Major progress has been attained in recent years in the understanding of the structures of these enzymes and their main cellular functions, hopefully providing new opportunities for pharmacological interventions. New leads and derivatives of known structures have been reported recently, and here they will be discussed highlighting the challenges to find innovative and more effective drugs. Moreover, we will review novel and diverse approaches relevant to the development of new topoisomerase-related therapeutics.

The mechanism of cytotoxicity of the camptothecin family of antitumor drugs is thought to be the consequence of a collision between moving replication forks and camptothecin-stabilized cleavable DNA-topoisomerase I complexes. One property of camptothecin analogs relevant to their potent antitumor activity is the slow reversal of the cleavable complexes formed with these drugs. The persistence of cleavable complexes with time may be an essential property for increasing the likelihood of a collision between the replication fork and a cleavable complex, giving rise to lethal DNA lesions. In this paper, we examined a number of camptothecin analogs forming cleavable complexes with distinctly different stabilities. Absolute reaction rate analysis was carried out for each derivative. Our results indicate that the stability of the cleavable complex is dominated by the activation entropy (DeltaS++) of the reversal process. We measured the relative lipophilicity of the CPT analogs by reverse-phase HPLC, but the DeltaS++ of complex reversal is not directly related to the lipophilicity of the CPT analog being used. We suggest that solvent ordering around the 7- through 10-position of the CPT ring may be responsible for reversal rate's dependence on DeltaS++. We demonstrate that the cleavable complex stability conferred by each camptothecin analog is directly correlated with the induction of apoptosis and cytotoxicity to tumor cells.

The present review discusses recent evidence on the mechanisms of formation of structural and numerical chromosome aberrations by anti-topoisomerase drugs. Among "cleavable complex"poisoning drugs, DNA topoisomerase II inhibitors induce DNA double strand breaks that lead to chromosomal aberrations independently of the phase of the cell cycle in which the treatment has been performed. Inhibitors of DNA topoisomerase I induce DNA single strand breaks that are transformed in DSB when the trapped "cleavable complex" collides with the replication fork, producing chromatid-type aberrations. Recently, ongoing chromosome condensation and RNA transcription have been shown to play a crucial role in the formation of chromatid-type aberrations by topoisomerase I poisons for treatments in the G(2) phase of the cell cycle. Mutations of single genes are also induced by anti-topoisomerase drugs. These consist mostly of deletions, duplications and insertions and are often localized at the topoisomerase cleavable sites. This suggests that alterations at the chromatin level may be responsible for inactivation of gene function after topoisomerase inhibitors. Anti-topoisomerase drugs promote also numerical chromosome aberrations as DNA topoisomerases are involved in chromosome condensation and segregation at mitosis. Polyploid cells are induced as a consequence of the total inhibition of sister chromatid separation before anaphase and aneuploid cells may arise when sister chromatid separation is defective. Gene mutations, chromosomal aberrations and aneuploidy may influence the stability of the genome further producing structural aand numerical aberrations at successive cell cycle divisions. Knowledge of the mechanisms producing gene mutations, chromosome aberrations and genomic instability after drugs interacting with topoisomerases is essential for developing effective therapeutical approaches.

The current lack of effective therapy for malignant gliomas has prompted the development of three primary foci of molecular research: anti-angiogenesis therapy, immunotherapy, and DNA- and RNA-based therapies. Angiogenesis inhibitors, designed to exploit the highly vascularized nature of gliomas, target endothelial cells and/or the extracellular matrix and bypass many of the problems of conventional chemotherapy. There may be easy access to the molecular target (e.g. blood vessels), reduced induction of drug resistance, and general lack of host toxicity. The relatively immunoprivileged status of the brain has also prompted use of immune stimulation as an anti-glioma strategy. Lines of attack include global cytokine therapy, vaccination with specific tumor antigens, dosing with monoclonal antibodies conjugated to radioisotopes or toxins, and ex vivo priming of lymphocytes. With regard to DNA- and RNA-based therapy, numerous oncogenic proteins have been targeted by antisense molecules administered alone or in combination with conventional chemotherapy and radiation. In one tactic, termed "suicide" gene therapy, herpes simplex thymidine kinase has been transfected into glioma cells via a retrovirus; subsequent introduction of ganciclovir causes cytotoxicity in the transduced cells. Although considerable preclinical data have been accumulated, promising results for therapy of human glioma have only recently appeared.

Prostaglandins (PGs) are involved in mediating or regulating many physiological as well as pathological processes. Important roles of PGs in the pathophysiology of carcinogenesis offer potentials of targeting PG synthesis and PG receptors in developing novel anti-cancer therapy. Although initial studies suggested direct growth inhibitory role of PGs from in vitro studies, it has been widely demonstrated that in general, PGs stimulate tumor growth. However, cyclopentenone PGs, especially 15d-PGJ2, which can activate peroxisome proliferator activated receptor (PPAR) gamma, exhibited anti-proliferative and proapoptotic effects on many types of cancer cells. But recent studies indicate that growth inhibitory effects of the cyclopentenone PGs might also be a nonspecific effect due to its highly reactive cyclopentenone ring. We have explored the published studies on PGs to specify its known regulatory roles on tumor growth with an objective of targeting the PGs or pathways activated by these lipids in treating cancers.

The lamellarins form a group of more than 30 polyaromatic pyrrole alkaloids, isolated from diverse marine organisms, mainly but not exclusively ascidians and sponges. These molecules fall in three structural groups, with the central pyrrole ring fused or unfused (lamellarins O-R) to adjacent aromatic rings and with the quinoline moiety containing a 5, 6-single--as in lamellarins I-L--or a double bond, as it is the case for lamellarins D and M which are both potent cytotoxic agents. The family also includes sulphated members, such as the integrase inhibitor lamellarin alpha 20-sulfate. This review presents the origin and structure of the lamellarins and summarizes the various chemical pathways which have been proposed to synthesize all lamellarins and different structurally related marine pyrrole alkaloids, including ningalins, storniamides and lukianols. The mechanisms of actions of these marine products are also discussed. Inhibition of HIV-1 integrase by lamellarin alpha 20-sulfate and human topoisomerase I by lamellarin D and Molluscum contagiosum virus topoisomerase by lamellarin H, along with other effects on nuclear proteins, provide an experimental basis indicating that DNA manipulating enzymes are important targets for the lamellarins. Some of these marine compounds exhibit cytotoxic activities against tumor cells in vitro and are insensitive to Pgp-mediated drug efflux. The structure-activity relationships are discussed. Other compounds in the series, without being strongly cytotoxic, can reverse the multidrug resistance phenotype and thus may be useful to promote the therapeutic activity of conventional cytotoxic drugs toward chemoresistant tumors. A complete description of the chemistry and pharmacological profiles of the lamellarins is presented here to shed light on this undervalued family of marine alkaloids.

Histone deacetylases (HDACs) play a critical role in gene transcription and have become a novel target for the discovery of drugs against cancer and other diseases. During the past several years there have been extensive efforts in the identification and optimization of histone deacetylase inhibitors (HDACIs) as novel anticancer drugs. Here we report a comprehensive quantitative structure-activity relationship (QSAR) study of HDACIs in the hope of identifying the structural determinants for anticancer activity. We have identified, collected, and verified the structural and biological activity data for 124 compounds from various literature sources and performed an extensive QSAR study on this comprehensive data set by using various QSAR and classification methods. A highly predictive QSAR model with R(2) of 0.76 and leave-one-out cross-validated R(2) of 0.73 was obtained. The overall rate of cross-validated correct prediction of the classification model is around 92%. The QSAR and classification models provided direct guidance to our internal programs of identifying and optimizing HDAC inhibitors. Limitations of the models were also discussed.

The conventional chemotherapy is mostly based on the evidence that proliferating cells are more sensitive to anticancer agents than non-dividing cells. This is the main reason why these compounds are not tumour specific and their selectivity is generally in favour of rapidly growing cells (haematopoietic or intestine. i.e.) rather than discriminating against any fundamental biological difference between normal and tumour cells. The critical issue is at present to identify how tumour cells differ from normal cells and how those differences can be exploited therapeutically for designing and synthesising new drugs with a selective mechanism of action and thus with an improved therapeutic index. This topic and the strategies to identify these new targets will be discussed in details in the review. The expanding knowledge on molecular biology of cancer cells has allowed in the last years the identification of different molecular pathways altered in cancer that could be exploited as potential therapeutic targets. For most of the pathways previously disclosed it has been a problem to develop selective molecules with a relevant clinic impact. To target those specific genetics defects, different kind of molecules (antibodies, "antisense oligonucleotides", short peptides and small molecules) have been made and some of them are currently under investigation. This review will be focused mainly on three different classes of compounds: I. Compounds designed to hit or inhibit crucial molecular targets. II. Novel DNA minor groove binders. III. Products of marine origin that exhibit novel mode of action.

While the cancer protective effect of soy-based diets has been the subject of numerous studies, the constituents of soy that may give rise to this effect remain elusive. Recent publications describing anticancer activity of crude and purified soybean saponins have sparked a renewed interest in these compounds. In this review, I summarize the epidemiological studies concerning the cancer protective effects of soy and the efforts to elucidate the constituents responsible for this effect. The recent reports of the anticancer activity of soy saponins is placed in context with reports of promising anticancer activity of structurally related non-dietary saponins from other legumes. While recent studies have demonstrated a direct effect of soy saponins on cancer cells, alternative mechanisms of cancer prevention by these agents are also discussed. It is concluded that the soy saponins may represent promising leads both in terms of elucidating the soy constituents involved in the cancer protective effect of soy as well as in the discovery of anticancer agents with novel mechanisms of action.