Advances in Anticancer Agents in Medicinal Chemistry

Chemical study of marine organisms has revealed them as a rich source of natural products with unique structural characteristics and outstanding biological activities. Marine macrolides are a unique group of natural products that frequently include a highly oxygenated polyene backbone and a macrocyclic lactone as a conformational constraint. Many of them have shown unparalleled cell growth antiproliferative properties, making them valuable molecular probes for the discovery of new biochemical pathways or as promising lead compounds in the development route to new antitumor chemotherapeutic agents. This bibliographic review has been focussed on marine macrolides with strong cytotoxic activity and potential in cancer research and therapy, as well as those macrolides either in the market or currently in clinical trials and/or preclinical development.

The research and development of organometallic supramolecular complexes as anticancer supramolecular drugs, which are aggregates mainly formed by one or more inorganic metal compounds with one or more either inorganic or organic molecules in general via coordination bonds, has been a quite rapidly developing, increasingly active and newly rising highlight interdisciplinary field. Numerous efforts have been directed toward organometallic supramolecular complexes as potential anticancer agents and the unprecedented progress has been made. This has opened up a wholly new and infinite space to create novel metal-based bioactive supermolecules. More importantly, metal-based complex supermolecules as potential anticancer agents with wide potential applications have become highlight topics in recent years, and are becoming increasingly useful and important in preventing and treating cancer diseases. In view of the rapid progress in organometallic complex anticancer supermolecules with rich variation of structural types, this work systematically reviewed the recent research and development of the whole range of metal-based supramolecular complexes as anticancer agents mainly since 2009. The perspectives of the foreseeable future and potential application of organometallic supramolecular complexes in cancer therapy were also presented. It is hoped that this review will serve as a stimulant for new thoughts in the quest for rational designs of more active and less toxic organometallic supramolecular complex anticancer drugs.

The unquestionable therapeutic success of the anticancer drug cisplatin and its second and third generation analogues has triggered, during the past fifty years, the development of several metal-based potential chemotherapeutic agents, most of which have unfortunately failed to enter clinical trials. In this context, since the late 1990s, the Biomedicinal Chemistry Research Group at the University of Padova (Italy) has been making quite an effort to design a number of metal-dithiocarbamato derivatives that were expected, at least in principle, to resemble the main features of cisplatin together with higher activity, improved selectivity and bioavailability, and reduced side-effects. Among all, some selected gold(III) complexes have been showing outstanding in vitro and in vivo antitumor properties and negligible (or even no) acute and renal toxicity, compared to the reference clinically-established platinum drugs.

Starting from the rationale behind such investigations, results achieved to date are here summarized, focusing on the in-depth mechanistic studies that have been providing insights into the mechanism of action of this class of metal compounds. New prospects opened up by these anticancer agents, including the latest development of “second generation” gold-based peptidomimetics for the targeted chemotherapy, are also illustrated and discussed.

Recent efforts in the design and synthesis of potential anti-cancer vaccines based on carbohydrates are outlined, covering literature up to 2012. This approach capitalises on the fact that cancer cells often display alterations in their glycan repertoire if compared to normal cells, resulting in the accumulation of new structures, usually referred as to tumour-associated carbohydrate antigens (TACA). Several preclinical and clinical studies demonstrate that naturally acquired, passively administered, or actively induced antibodies against TACAs are able to eliminate circulating tumour cells and micro-metastases in cancer patients. TACAs can be ideal candidates to elicit an antitumor immune response, however they are often not immunogenic enough to induce protection, since many of them are of embryonic origin or expressed in normal tissue, even if at low levels, and consequently tolerated by the immune system. Approaches toward breaking self-tolerance in the design of novel glycocnjugates structures, together with new conjugation methods appeared in the last years will be considered.

Isatin (1H-indole-2,3-dione) and its derivatives are responsible for a broad spectrum of biological activities. Among these the cytotoxic and antineoplastic properties have been the most widely reported. The synthetic versatility of the isatin, due to its privileged scaffold, has led to the generation of a large number of structurally diverse derivatives which include analogues derived from either mono-, di-, and trisubstitution of the aryl ring A, and/or those obtained by derivatisation of the isatin nitrogen and C2/C3 carbonyl moieties. These compounds inhibit cancer cell proliferation and tumour growth via interaction with a variety of intracellular targets such as DNA, telomerase, tubulin, P-glycoprotein, protein kinases and phosphatases. Herein we review recent highlights in the development of isatin-based compounds as anticancer agents with a particular focus on the cytotoxicity and structure activity relationships.

The 8H-thieno[2,3-b]pyrrolizinones, some of which exert very potent cytotoxic activity against tumor cell lines in vitro, are a promising novel series of anticancer agents. These compounds belong to the tripentone family and are based on 9Hpyrrolo[ 1,2-a]indol-9-one derivatives and their heterocyclic isosteres. This paper inventories the different synthetic strategies for tripentones and reviews their biological effects and therapeutic potential.

Estrogen is important in human health and diseases. Estrogen binds to estrogen receptors (ER), alpha and beta which subsequently function as transcription factors. Selective estrogen receptor modulators (SERMs) are synthetic molecules which bind to ER and can modulate its transcriptional capabilities in different ways in diverse estrogen target tissues. Tamoxifen, the first SERM, is extensively used for targeted therapy of ER positive breast cancers and is also approved as the first chemo-preventive agent for lowering breast cancer incidence in high risk women. The strategy for the therapeutic and preventive applications of tamoxifen was initially demonstrated in the laboratory which laid the foundation for its success in the clinic. Unfortunately, use of tamoxifen is associated with de novo and acquired resistance and some undesirable side effects. The molecular study of the resistance provides an opportunity to understand the mechanism of SERM action which may further help in designing new and improved SERMs. Clinical studies demonstrate that another SERM, raloxifene, used to treat postmenopausal osteoporosis, is also as efficient as tamoxifen in preventing breast cancers with fewer side effects. Overall, these findings provide opportunities for SERMs as a new class of drugs which not only can be used for therapeutic and preventive purposes of breast cancers but also for other disease states. The goal is to create new SERMs with a better therapeutic profile and fewer side effects.

Chronic myeloid leukemia (CML) is induced by the BCR-ABL oncogene, a product of Philadelphia (Ph) chromosome. The BCR-ABL kinase inhibitor imatinib is a standard treatment for Ph+ leukemia, and has been shown to induce a complete hematologic and cytogenetic response in most chronic phrase CML patients. However, imatinib does not cure CML, and one of the reasons is that imatinib does not kill leukemia stem cells (LSCs) in CML both in vitro and in vivo. Recently, several new targets or drugs have been reported to inhibit LSCs in cultured human CD34+ CML cells or in mouse model of BCR-ABL induced CML, including an Alox5 pathway inhibitor, Hsp90 inhibitors, omacetaxine, hedgehog inhibitor and BMS-214662. Specific targeting of LSCs but not normal stem cell is a correct strategy for developing new anti-cancer therapies in the future.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in humans. Despite aggressive surgical resection using state-of-theart neuroimaging and radiochemotherapy, the prognosis of GBM remains poor, with an estimated median survival of 12-14 months. At presentation, tumor cells have already have migrated into normal brain tissue beyond the main tumor mass. This accounts for the inability of surgery to cure this tumor. It is therefore imperative to better understand how inhibit GBM cell migration. In this review, we describe various potential targets that may be exploited to inhibit the migration GBM cells.

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) was initially discovered as an enzyme that catalyzes the hydrolysis of 3’-phosphotyrosyl bonds. Such linkages are transiently introduced in vivo by the DNA processing activity of topoisomerase I (Top1). For this reason, Tdp1 has been implicated in the repair of irreversible Top1- DNA covalent complexes (Top1cc), which can be generated by either exogenous or endogenous factors. Tdp1 has been regarded as a potential therapeutic co-target of Top1 in that it seemingly counteracts the effects of Top1 inhibitors, such as camptothecin and its clinically used derivatives. Thus, by reducing the repair of Top1-DNA lesions, Tdp1 inhibitors have the potential to augment the anticancer activity of Top1-targeting drugs. Tdp1 inhibitors may also selectively target cancer cells with defects in alternative repair pathways for Top1cc, e.g. DNA checkpoint and repair pathways. Human Tdp1 can also hydrolyze other 3’-end DNA alterations including 3’-phosphoglycolates and 3’-abasic sites indicating it may function as a general 3’-end processing repair enzyme. The importance of Tdp1 in humans is highlighted by the observation that a recessive mutation in the human Tdp1 gene is responsible for the inherited disorder, spinocerebellar ataxia with axonal neuropathy (SCAN1). This review provides a summary of the biochemical and cellular processes performed by Tdp1 as well as the rationale behind the development of Tdp1 inhibitors for anticancer therapy.