Modern and Emerging Perspectives on Natural Product Utilisation

NATURAL PRODUCTS, DERIVATIVES AND MIMICS AS ANTITUMOUR AGENTS

David J. Newman and Gordon M. Cragg

Natural Products Branch, Developmental Therapeutics Program, NCI-Frederick, P. O. Box B, Frederick, MD, 21702, USA

(Note: The opinions expressed in this article are the opinions of the authors, not necessarily those of the US Government)

1 INTRODUCTION

From early in the 1940s, the quest for agents that may ameliorate the scourge of the manifold diseases clustered under the term cancer, has involved all aspects of chemistry and pharmacology and throughout all these years, compounds from natural sources, microbes, plants, and latterly, marine invertebrates, have played an extremely important part.

The roles played by these natural products have changed with time and the increase of scientific knowledge. Thus, their initial role was as the major source of drugs used for direct treatment. This was followed by use as active scaffolds upon which chemists would practice their skill and in current times, natural products and derivatives are acting as modulators of specific cellular pathways in the tumour cell.

Currently, the 164 (as of June 2009) small molecule compounds available to the physician (depending upon their individual country) as antitumour agents can be categorized as follows: N (natural products: 25; 17%), ND (natural product-derived, usually semi-synthetic modifications: 50; 31%), S (totally synthetic drugs: 42; 26%), S/NM (synthetic drugs/natural product mimics: 16; 10%), S* (synthetic drugs inspired by natural products: 20; 12%) and S*/NM (synthetic drugs inspired by natural products/natural product mimics: 7; 4%), using the nomenclature of Newman et al. Recently another author, using a somewhat different series of definitions where only "direct and slightly modified natural products are counted as such", has shown the influence of natural product scaffolds using a different schematic and readers should consult Bailly's article for further information.

As a further refinement, the influence of microbial secondary metabolites on approved agents in cancer treatment can be seen in Table 1. Of the 47 commercially available compounds listed (including everolimus, which was approved for anticancer use after being approved for immunosuppression), 26 (or 55%) are either directly from microbes or are derivatives of microbial secondary metabolites. Trabectedin 1 is probably from microbial commensals rather than from the marine tunicate, Ecteinascidia turbinata. The remaining 21 agents (45%) are nominally synthetic but the major proportion are either modified nucleosides whose chemical antecedents can be traced back to Bergmann's discoveries of marine-sourced nucleosides containing arabinose, or are isosteres of ATP.

Since the full history of such sources with their manifold digressions into chemical and pharmacological space would be a massive undertaking, we have elected to highlight the influence of certain natural product classes that have derivatives in or approaching clinical trials in order to demonstrate how even today, in the midst of massive efforts related to combinatorial chemical techniques coupled to rational drug design, natural products from many ecological niches are still a major source of novel scaffolds upon which to base potential antitumour agents. For a discussion of the earlier history and derivation of the major classes of compounds derived from nature that are in current use, the reader is directed to the 2005 compendium on Anticancer Agents from Natural Products and the articles therein.

Due to space constraints generally we will discuss only the agents that are currently in Phase II and Phase III clinical trials in general, though where a particular class of compounds spans the range from preclinical to Phase III, we will include most of the molecules in order to demonstrate the breadth of possibilities.

2 NON-MARINE MICROBIAL AGENTS CURRENTLY IN CLINICAL TRIALS

Currently there are at least 17 agents derived from identified microbial sources in various clinical trials against a wide variety of human tumours in both paediatric and adult patients. These encompass structures based on staurosporins, anthracyclines, and bicyclic thiobridged compounds, with mechanisms of action (MOA) including inhibitors of topoisomerase I, II and histone deacetylase (HDAC).

2.1 Staurosporin Based Molecules

Staurosporin 2 is a pan-protein kinase C (PKC) inhibitor and the role of the base structure is evident if one looks at the number of derivatives that are in clinical trials at this moment. Becatecarin 3, a rebeccamycin 4 analogue with a sugar moiety that has been extensively modified, is claimed not to be a PGP substrate, though it is transported by ABCG2 and can induce ABCG2 expression in cancer cells. It is in trials for leukaemia and other tumour types both with and without other cytotoxins. A recent report shows efficacy in a Phase II trial against advanced biliary cancers with an overall response rate (partial response in 5% and stable disease in 35%) of 40%, which has encouraged extension to a Phase III trial in due course. A current listing of trials with this agent can be found via the "clinicaltrials.gov" web site and data in early 2009 can also be found in the "Gateways to Clinical Trials" report by Tomillero and Moral.

A reasonably close relative to staurosporin is the indolocarbazole K-252a 5, derivatives of which have been placed into clinical trials in neurodegenerative diseases as well as in cancer. For cancers, the simple derivative lestaurtinib 6 is currently in five trials, with four being at the Phase II level (two in myelofibrosis and one each in acute myelogenous leukaemia and polycythemia vera), and one at Phase I (paediatric neuroblastoma). The same basic structure is also in Phase II/III clinical trials as midostaurin 7 and the ring-opened version of staurosporin, known as enzastaurin 8, is in multiple Phase II trials with some recent positive effects 11 and has reportedly just entered Phase Ill trials in lymphoma. Enzastaurin also has potential in the treatment of human transitional cell carcinoma in a preclinical model with gemcitabine. Although not formally an antitumour compound, the modified maleimide, sotrastaurin 9 is also a PKC inhibitor and is in Phase II trials for psoriasis, which is a skin disease that antitumour agents may well help in controlling. This compound also has activity as an immunomodulator and is in Phase II clinical trials for this indication as well. Whether it will follow in the footsteps of the rapamycin analogues (see below) has yet to be determined.

2.2 Anthracycline Based Molecules

The anthracyclines, isolated from bacteria of the order Actinomycetales, are probably the most utilized microbial chemical class of antitumour agents, both directly from nature and as semi-synthetic modifications,...