Novel antitumor agents: marine sponge alkaloids, their synthetic analogs and derivatives

Present review describes research on novel natural antitumor agents isolated from marine sponges. More than 90 novel cytotoxic antitumor compounds and their synthetic analogs have shown confirmed activity in vitro tumor cell lines bioassay and are of current interest to NCI for further in vivo evaluation. A great problem, to use directly the reservoir of marine organisms for therapy is the very low availability and the isolation of only very small amounts of the biologically active substances from the natural materials. Thus, the synthetic chemistry is required to develop high yield synthetic methods, which are able to produce sufficient marine alkaloids for a broad biological screening. This review will present some of the aspects of the medicinal chemistry developed recently to introduce such modifications. The structures, origins, synthesis and biological activity of a selection of N-heterocyclic marine sponge alkaloids are reviewed. The emphasis is on compounds poised as potential anticancer drugs: pyrroles, pyrazines, imidazole, and other structural families. With computer program PASS some additional biological activities are also predicted, which point toward new possible applications of these compounds. This review emphasizes the role of marine sponge alkaloids as an important source of leads for drug discovery.     

Recent anticancer cytotoxic agents

In spite of the impressive progress in diagnosis, surgery and therapy that occurred since the Sixties, the overall cancer mortality is still high and the medical need is largely unmet. A number of innovative strategies, aimed to target malignant abnormalities of tumor cells are in development and begin to give important results. In alternative, angiogenesis inhibition has been addressed with the aim to limit the tumor ability to grow and metastasize. However, it will likely take some years to fully define the therapeutic role of different innovative drugs. Therefore, cytotoxic drugs will continue to represent a chief part of the therapy in the forthcoming years, possibly in combination with innovative agents addressing molecular targets. Most important traditional chemotherapeutic drugs or investigational anticancer agents were derived from natural sources also through synthetic structural modifications. In the Nineties, taxanes and camptothecins represented important success stories of this approach, while among DNA interacting agents anthracyclines continued to represent a structural platform for discovering new drugs and DNA minor groove binders represented a new field of investigation. Combinatorial chemistry combined with high-throughput screening programs are an important source of totally synthetic new agents, however, it should not be disregarded the fact that nature already performed combinatorial chemistry and leads selection through the ages. New natural or semisynthetic agents acting as tubulin stabilizers or DNA interactive agents of various mechanisms of action are presently investigated and will probably continue to give important contribution to cancer therapy in the near future. In this review, the medicinal chemistry and the development status of these anticancer cytotoxic agents are focused and discussed.     

Marine-derived anticancer agents in clinical trials

Anticancer agents may be derived either from the isolation of an active lead compound occurring spontaneously in nature or by novel chemical synthesis in the laboratory. There are examples of successful drugs being derived from both sources, which have had a profound impact on the natural history of various types of cancer. The treatment of lymphomas and acute leukaemias with the use of combination chemotherapy, including anthracyclines and vinca alkaloids, are examples of the contribution of nature. In contrast, agents such as 5-fluorouracil, methotrexate and more recently, the humanised anti-CD20 antibody rituximab and the tyrosine kinase inhibitor imatinib are examples of synthetic compounds, which were designed with a clear rationale, that are routinely used in patients with solid tumours and haematological malignancies. Until recently, the tradition in natural product-derived anticancer drug development was to rely almost exclusively on the screening of terrestrial sources (plant extracts and fermentation products) for their cytotoxic properties. Although C-nucleosides obtained from Caribbean sponge were the initial inspiration for the synthesis of antiviral substituted nucleosides and the successful anticancer agent citarabine, active against leukaemias and lymphomas, the contribution of marine compounds as a source of anticancer agents was modest. In recent years, the improvements in the technology of deep-sea collection and aquaculture added to the growing recognition of the tremendous biodiversity present in the marine world, and has contributed to the growing interest of exploring the oceans as a potential source of new anticancer candidates. This is reflected in the number of marine-derived compounds undergoing preclinical and early clinical development. In this paper, the authors discuss the available literature on anticancer agents that have reached clinical trials, such as didemnin B, aplidine, dolastatin-10, bryostatin-1 and ecteinascidin-743 (ET-743, trabectedin), as well as other promising compounds still undergoing tests in the laboratory.     

Marine-derived anticancer agents in clinical trials

Anticancer agents may be derived either from the isolation of an active lead compound occurring spontaneously in nature or by novel chemical synthesis in the laboratory. There are examples of successful drugs being derived from both sources, which have had a profound impact on the natural history of various types of cancer. The treatment of lymphomas and acute leukaemias with the use of combination chemotherapy, including anthracyclines and vinca alkaloids, are examples of the contribution of nature. In contrast, agents such as 5-fluorouracil, methotrexate and more recently, the humanised anti-CD20 antibody rituximab and the tyrosine kinase inhibitor imatinib are examples of synthetic compounds, which were designed with a clear rationale, that are routinely used in patients with solid tumours and haematological malignancies. Until recently, the tradition in natural product-derived anticancer drug development was to rely almost exclusively on the screening of terrestrial sources (plant extracts and fermentation products) for their cytotoxic properties. Although C-nucleosides obtained from Caribbean sponge were the initial inspiration for the synthesis of antiviral substituted nucleosides and the successful anticancer agent citarabine, active against leukaemias and lymphomas, the contribution of marine compounds as a source of anticancer agents was modest. In recent years, the improvements in the technology of deep-sea collection and aquaculture added to the growing recognition of the tremendous biodiversity present in the marine world, and has contributed to the growing interest of exploring the oceans as a potential source of new anticancer candidates. This is reflected in the number of marine-derived compounds undergoing preclinical and early clinical development. In this paper, the authors discuss the available literature on anticancer agents that have reached clinical trials, such as didemnin B, aplidine, dolastatin-10, bryostatin-1 and ecteinascidin-743 (ET-743, trabectedin), as well as other promising compounds still undergoing tests in the laboratory.     

Seek and destroy: the use of natural compounds for targeting the molecular roots of cancer

One of the major issues facing anticancer research relies on the intrinsic inability of tumor cells to undergo apoptosis. Additionally, the development of cancer resistance to standard therapy and the great heterogeneity associated with frequent mutations and epigenetic changes make an ever increasing challenge to achieve treatment success. Thus, novel therapeutic approaches to induce cancer demise must be explored. Compelling evidence has shown the ability of naturally-occurring compounds to modulate signal transduction pathways, apoptosis and cell cycle progression, supporting their relevance to anticancer drug discovery. Moreover, millions of years of biological selection have led to an unlimited repertoire of chemical structures unmatched by any synthetic combinatorial library and recent advances in the fields of chemistry and biology are uncovering this still underexplored source of new promising natural agents, opening novel perspectives for the development of alternative strategies to fight cancer. This review presents the current status of natural products in modern oncology, illustrating the importance of some old and new agents, such as antimitotics and apoptosis inducers, as candidates of pharmacological interest in drug development and/or as chemical tools for the elucidation, as well as targeting, of deregulated cancer signaling pathways. Finally, some aspects of chemical modifications done in natural products core aiming to improve their activity and/or effectiveness will be discussed.     

Antineoplastic agents from natural sources: achievements and future directions

The influence of natural products upon anticancer drug discovery and design cannot be overestimated. Approximately 60% of all drugs now in clinical trials for the multiplicity of cancers are either natural products, compounds derived from natural products, contain pharmacophores derived from active natural products or are 'old drugs in new clothes', where (modified) natural products are attached to targeting systems. This review covers those materials that the authors are aware of as being in clinical trials through early 2000 and demonstrates how, even today, in the presence of massive numbers of agents from combinatorial libraries, the compounds produced by 'Mother Nature' are still in the forefront of cancer chemotherapeutics as sources of active chemotypes.     

Antineoplastic agents from natural sources: achievements and future directions

The influence of natural products upon anticancer drug discovery and design cannot be overestimated. Approximately 60% of all drugs now in clinical trials for the multiplicity of cancers are either natural products, compounds derived from natural products, contain pharmacophores derived from active natural products or are ‘old drugs in new clothes’, where (modified) natural products are attached to targeting systems. This review covers those materials that the authors are aware of as being in clinical trials through early 2000 and demonstrates how, even today, in the presence of massive numbers of agents from combinatorial libraries, the compounds produced by ‘Mother Nature’ are still in the forefront of cancer chemotherapeutics as sources of active chemotypes.     

中草药中发现新抗癌药物的途径

中草药的使用已有数千年的历史,对于各种疾病包括肿瘤的治疗都取得了十分宝贵的人体经验.丰富的中草药资源也为寻找新抗癌药提供了重要的物质基础.从传统中医药理论结合现代科学发现从4个方面阐述了进一步从中草药中发现新抗癌药的途径,以期对天然产物来源的新抗癌药物的发现起到一定的启发与促进作用.这4个方面分别是:根据传统中医理论发现抗癌药,包括清热解毒药、活血化瘀药、调节免疫药(补气扶正药)及有毒中草药(以毒攻毒);从近年发现的抗肿瘤先导化合物中寻找;通过普筛或高通量筛选从中草药提取物中寻找和依据药用植物亲缘学的原理寻找.     

Recent cancer drug development with xanthone structures

Objectives Xanthones are simple three‐membered ring compounds that are mainly found as secondary metabolites in higher plants and microorganisms. Xanthones have very diverse biological profiles, including antihypertensive, antioxidative, antithrombotic and anticancer activity, depending on their diverse structures, which are modified by substituents on the ring system. Although several reviews have already been published on xanthone compounds, few of them have focused on the anticancer activity of xanthone derivatives. In this review we briefly summarize natural and synthetic xanthone compounds which have potential as anticancer drugs. Key findings The interesting structural scaffold and pharmacological importance of xanthone derivatives have led many scientists to isolate or synthesize these compounds as novel drug candidates. In the past, extensive research has been conducted to obtain xanthone derivatives from natural resources as well as through synthetic chemistry. Xanthones interact with various pharmacological targets based on the different substituents on the core ring. The anticancer activities of xanthones are also dramatically altered by the ring substituents and their positions. Summary The biological activities of synthetic xanthone derivatives depend on the various substituents and their position. Study of the biological mechanism of action of xanthone analogues, however, has not been conducted extensively compared to the diversity of xanthone compounds. Elucidation of the exact biological target of xanthone compounds will provide better opportunities for these compounds to be developed as potent anticancer drugs. At the same time, modification of natural xanthone derivatives aimed at specific targets is capable of expanding the biological spectrum of xanthone compounds.     

Natural products in drug discovery

Natural products have been the single most productive source of leads for the development of drugs. Over a 100 new products are in clinical development, particularly as anti-cancer agents and anti-infectives. Application of molecular biological techniques is increasing the availability of novel compounds that can be conveniently produced in bacteria or yeasts, and combinatorial chemistry approaches are being based on natural product scaffolds to create screening libraries that closely resemble drug-like compounds. Various screening approaches are being developed to improve the ease with which natural products can be used in drug discovery campaigns, and data mining and virtual screening techniques are also being applied to databases of natural products. It is hoped that the more efficient and effective application of natural products will improve the drug discovery process.     

Recent advances in the generation of chemical diversity libraries

In recent years, screening in combination with a diverse compound collection has become a powerful method for discovering leads for the ever-increasing number of new biologically active peptides, proteins, receptors, and enzymes discovered continually. As a result, the rapid generation and screening of compound libraries (collections) have recently become important major tools in the search for novel lead structures. Diverse collections of compounds have been acquired by many strategies; these include (1) natural products from plants, fermentation, marine organisms, insect toxins, and ethnic pharmacotherapies; (2) recombinant randomized peptide libraries (often referred to as biological diversity); (3) multiple peptide synthesis; and (4) non-peptidic synthetic libraries. The present review provides an overview of the recent advances in the field of peptide and non-peptidic synthetic libraries. The progress made thus far is broadly divided into two categories: (1) Amide based libraries. These libraries share the concepts of the peptide library strategies; much of the referenced work thus refers to peptides, reflecting the bias of the literature to date. (2) Non-amide based libraries. This promising technology combines solid phase synthesis with classical organic synthesis to provide large numbers of compounds with desirable bioavailability and pharmacokinetics for screening. The basic premise behind the second approach is that the high affinity ligands, when identified, will be much more likely to become useful therapeutic agents than the compounds discovered from amide based libraries. Synthesizing small heterocyclic ring systems that use ligands of diverse biological activity via combinatorial strategies is a fast developing branch of medicinal chemistry. We are at an early state in the development of combinatorial chemistry. However, this dramatic convergence of technologies represents a fundamental advance in medicinal chemistry and promises to play a major role in future drug discovery efforts. © 1994 Wiley-Less, Inc.     

Design and synthesis of some thieno[2,3-c]pyridazine derivatives of expected anticancer activity

Design and synthesis of some new thienopyridazine derivatives as anticancer agents were the goal of this work. Accordingly, a series of novel compounds were synthesized via reacting thienopyridazine carboxylic acid hydrazide with different organic reagents. Twelve novel compounds were selected by National Cancer Institute for a full anticancer screening assay where seven of the investigated compounds showed non-selective broad spectrum and promising activity almost against all cancer cell lines. One of the most active compounds was chosen to be evaluated against 60-cell line panel at five concentration levels and revealed a remarkable growth inhibition activity.     

有机硫类抗真菌药物的研究进展

抗真菌药物(antifungal drugs)是一种用于治疗真菌感染的有效药物。近年来,天然抗真菌化合物的筛选和合成抗真菌药物的结构修饰促进了有机硫类抗真菌药物迅速发展。文中对天然有机硫类抗真菌化合物的研究进展进行了综述,同时从氮唑类、硫脲类和丙烯胺类以及硫色酮类等3类化合物的结构修饰方面综述了目前合成有机硫类抗真菌药物的研究进展。     

Screening and evaluation of anticancer agents

The screening and evaluation procedures for the development of anticancer agents indicated that the entire process is a rather difficult task. This is particularly true in choosing screening models and criteria for activity. If the criteria were set too low, then some clinically false-positive results may be faced; and if the criteria were set too high, some agents could be missed which might be effective against certain types of human cancer. Presently, active compounds are selected by prescreening and screening against transplanted mouse tumors and human tumor xenografts as well as by the in vitro systems. Xenografts of human tumor in athymic nude animals represent metabolic characteristics of human malignant disease which appear to be of value in the preclinical screening. Human tumor cloning assays have gained increased attention as a promising in vitro test system for the screening as well as for the prediction of patient responses. Application of chemosensitivity tests in the prediction of the responses of individuals to chemotherapy, especially in the identification of drug resistant tumors are, in general, quite reliable. Human tumor xenografts, human tumor cloning assays and chemosensitivity tests may be regarded as the major impetus in screening during the past decade. After promising agents are selected from the screening procedures, before the filing of an investigational new drug application, the preclinical toxicology and pharmacology should be completed. Information on the nature of toxicity, dose-response effects, and dose schedule are necessary for predicting the effects of the drug in man. The new drugs then go through three phases of clinical trials to assure safety, effectiveness, and reliability of the drugs. During the past fifteen years eight-three antineoplastic drugs were evaluated clinically under the NCI sponsorship and twenty-four are active in at least one disease. Among these active drugs, eleven possess novel clinical structure, the remaining thirteen are analogues of known active compounds already in clinical trials. After an investigational anticancer drug is approved by the U.S. Food and Drug Administration it becomes a commercial product on the market and the benefits can be shared by the general public. The time required for evaluation and development from the first discovery of activity to final FDA approval for fifty-two therapeutic drugs are tabled. The average interval is 8.8 years, but in the 1950s the average was only 2.8 years, in the 1960s, 6.5 years; in the 1970s, 13.9 years; and in the 1980s, 16.0 years. This reflects the increasing stricter requirements for an antineoplastic drug to be officially recognize     

Timely synthetic support for medicinal chemists

In recent years, there have been significant developments made in the way new drugs are being discovered and developed. Such changes are driven by new technologies that have expanded the opportunities to prepare and screen large libraries of compounds in a rapid time frame by the use of high-throughput synthesis and screening techniques [1-3]. These strategies are driven by the need to shorten time lines for bringing discovery leads to the market [4,5]. As a result, the role and needs of synthetic chemistry in the discovery and development of new therapeutic agents has been altered [6]. This paper will explore the roles of synthetic chemists and how pharmaceutical companies respond to the evolving needs of synthetic chemistry challenges in their discovery and development programs.     

Platinum group antitumor chemistry: design and development of new anticancer drugs complementary to cisplatin

In the next two decades, the world is expected to see around 20 million cases of cancer. Moreover, the types of cancer will vary considerably from country to other. Therefore, all efforts will be needed to face such a vast diversity of problems. With current annual sales of about $500 millions, the platinum(II) complex known as cisplatin [cis-(NH3)2PtCl2] is still one of the most effective drugs to treat testicular, ovarian, bladder and neck cancers. Since it was launched in 1978 there has been a rapid expansion in research to find new, more effective metal-based anticancer drugs and to study their interactions with biological systems. This study gives an up to date overview of the anticancer chemistry of the platinum group elements platinum, palladium, and nickel with an emphasis on the new strategies used in the development of new antitumor agents. Methodologies for application of bulky aromatic or aliphatic nitrogen ligands, chiral organic moieties, chelates containing other donor atoms than nitrogen, and biologically active ligands in the design of agents analogous to cisplatin are presented. The review also aims to highlight the class of the unconventional complexes that violate the empirical structure-activity rules (SAR) of platinum compounds and the common features and structural differences between the most successful anticancer complexes that are currently in human clinical trials.     

Biochemical and pharmacological characterization of isatin and its derivatives: from structure to activity

Isatin, 1H-indole-2,3-dione, is a heterocyclic compound of significant importance in medicinal chemistry. It is a synthetically versatile molecule, a precursor for a large number of pharmacologically active compounds. Isatin and its derivatives have aroused great attention in recent years due to their wide variety of biological activities, relevant to application as insecticides and fungicides and in a broad range of drug therapies, including anticancer drugs, antibiotics and antidepressants. The purpose of this review is to provide an overview of the pharmacological activities of isatin and its synthetic and natural derivatives. Molecular modifications to tailor the properties of isatin and its derivatives are also discussed.     

An overview of quinoline as a privileged scaffold in cancer drug discovery

Introduction: The concept of privileged structures is well known and is often used in the process of drug design and development. Although its assumptions are not clear, its overall usefulness remains high. Various substructures have been identified as privileged and quinoline is a prime example of such a structure.

Areas covered: Quinoline drugs that are currently approved or under clinical investigation were reviewed based on a literature search. Their modes of action and outcomes during clinical research are discussed.

Expert opinion: Undoubtedly, quinoline-based compounds have a significant impact on anticancer drugs. Although topoisomerase and kinase inhibitors are the only two different classes of agents that are currently approved for anticancer therapy, more than twenty different drug candidates are being tested on humans. The quinoline moiety offers an easily accessible, well-understood scaffold for designing new drugs. It is also a very druggable molecule with the potency for structure optimization through established synthetic pathways. For these reasons, quinoline-based anticancer drugs have a strong position in modern medicinal chemistry.     

Anticancer prodrugs: an overview of major strategies and recent developments

Research in anticancer chemotherapy has produced outstanding results, and mean survival rates have significantly improved over the last ten years. Nevertheless, all approved drugs are still characterized by narrow therapeutic windows that result mainly from their high systemic toxicity combined with their marked lack of tumor selectivity. Medicinal chemistry responds to the resulting demands with new analogues of a lead drug, or by developing prodrugs. Prodrugs are inactive compounds, which are metabolized in the body, either chemically or enzymatically, in a controlled or predictable manner, to the active parent drug. This review describes the results of strategies in prodrug development, subdivided into the principal categories of anticancer agents. The chemical implementation of prodrug approaches is illustrated through selected drug candidates.