Since its approval in 1979 cisplatin has become an important component in chemotherapy regimes for the treatment of ovarian, testicular, lung and bladder cancers, as well as lymphomas, myelomas and melanoma. Unfortunately its continued use is greatly limited by severe dose limiting side effects and intrinsic or acquired drug resistance. Over the last 30 years, 23 other platinum-based drugs have entered clinical trials with only two (carboplatin and oxaliplatin) of these gaining international marketing approval, and another three (nedaplatin, lobaplatin and heptaplatin) gaining approval in individual nations. During this time there have been more failures than successes with the development of 14 drugs being halted during clinical trials. Currently there are four drugs in the various phases of clinical trial (satraplatin, picoplatin, Lipoplatin™ and ProLindac™). No new small molecule platinum drug has entered clinical trials since 1999 which is representative of a shift in focus away from drug design and towards drug delivery in the last decade. In this perspective article we update the status of platinum anticancer drugs currently approved for use, those undergoing clinical trials and those discontinued during clinical trials, and discuss the results in the context of where we believe the field will develop over the next decade.

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The status of platinum anticancer drugs in the clinic and in clinical trials.

Although traditionally natural products have played an important role in drug discovery, in the past few years most Big Pharma companies have either terminated or considerably scaled down their natural product operations. This is despite a significant number of natural product-derived drugs being ranked in the top 35 worldwide selling ethical drugs in 2000, 2001, and 2002. There were 15 new natural product-derived drugs launched from 2000 to 2003, as well as 15 natural product-derived compounds in Phase III clinical trials or registration at the end of 2003. Recently, there has been a renewed interest in natural product research due to the failure of alternative drug discovery methods to deliver many lead compounds in key therapeutic areas such as immunosuppression, anti-infectives, and metabolic diseases. To continue to be competitive with other drug discovery methods, natural product research needs to continually improve the speed of the screening, isolation, and structure elucidation processes, as well addressing the suitability of screens for natural product extracts and dealing with issues involved with large-scale compound supply.

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The Role of Natural Product Chemistry in Drug Discovery

Natural products have inspired chemists and physicians for millennia. Their rich structural diversity and complexity has prompted synthetic chemists to produce them in the laboratory, often with therapeutic applications in mind, and many drugs used today are natural products or natural-product derivatives. Recent years have seen considerable advances in our understanding of natural-product biosynthesis. Coupled with improvements in approaches for natural-product isolation, characterization and synthesis, these could be opening the door to a new era in the investigation of natural products in academia and industry.

Lessons from natural molecules

Traditional cancer chemotherapy is often accompanied by systemic toxicity to the patient. Monoclonal antibodies against antigens on cancer cells offer an alternative tumor-selective treatment approach. However, most monoclonal antibodies are not sufficiently potent to be therapeutically active on their own. Antibody-drug conjugates (ADCs) use antibodies to deliver a potent cytotoxic compound selectively to tumor cells, thus improving the therapeutic index of chemotherapeutic agents. The recent approval of two ADCs, brentuximab vedotin and ado-trastuzumab emtansine, for cancer treatment has spurred tremendous research interest in this field. This Review touches upon the early efforts in the field, and describes how the lessons learned from the first-generation ADCs have led to improvements in every aspect of this technology, i.e., the antibody, the cytotoxic compound, and the linker connecting them, leading to the current successes. The design of ADCs currently in clinical development, and results from mechanistic studies and preclinical and clinical evaluation are discussed. Emerging technologies that seek to further advance this exciting area of research are also discussed.

Antibody-drug conjugates: an emerging concept in cancer therapy

Multidrug Resistance Proteins (MRPs), together with the cystic fibrosis conductance regulator (CFTR/ABCC7) and the sulfonylurea receptors (SUR1/ABCC8 and SUR2/ABCC9) comprise the 13 members of the ...

Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins

Calichemicins, a novel family of antitumor antibiotics. 2. Chemistry and structure of calichemicin .gamma.1I

Calicheamicins, a novel family of antitumor antibiotics. 4. Structure elucidation of calicheamicins .beta.1Br, .gamma.1Br, .alpha.2I, .alpha.3I, .beta.1I, .gamma.1I, and .delta.1I

New (malonato)platinum(II) compounds, cis-[Pt(OOCACOO)(Me 2 SO) 2 ] (A=CH 2 , cycloalkyl), have been prepared, and their reactions with various amines have led to a new general synthesis of antitumor symmetrical and dissymmetrical (malonato)platinum(II) complexes. Reaction of trans-(―)-1,2-cyclohexanediamine (CHDA) with the cyclobutanedicarboxylate (CBDC) complex cis-[Pt(CBDC)(Me 2 SO) 2 ] has been studied in detail, and crystallographic molecular structure determinations have been carried out on the Pt(CHDA)(Me 2 SO)(CBDC) intermediate and the Pt(CHDA)(CBDC) product

(Malonato)bis[sulfinylbis[methane]-S]platinum(II) compounds: versatile synthons for a new general synthesis of antitumor symmetrical and dissymmetrical (malonato)platinum(II) complexes

The synthesis, stability, and antitumor activity of a series of water-soluble third generation platinum(II) complexes have been described. Among these complexes, [2,2-bis(aminomethyl)-1,3- propanediol-N,N'] [1,1-cyclobutanedicarboxylato(2-)-O,O']platinum(II) and [1,1-cyclobutanedicarboxylate(2-)-O,O'](tetrahydro-4H-pyran-4,4- dimethanamine-N,N'-)platinum(II) have shown the greatest promise for further investigation and are currently under clinical evaluation.

Water-soluble third generation antitumor platinum complexes, [2,2-bis(aminomethyl)-1,3-propanediol-N,N']-[1,1-cyclobutanedicarboxylato(2-)-O,O']platinum(II) and [1,1-cyclobutanedicarboxylato(2-)-O,O'][tetrahydro-4H-pyran-4,4-dimethanamine-N,N']platinum(II)

The nitro group of dioxapyrrolomycin (1) was shown to be introduced via direct biochemical nitration in cultures of the producing organism Streptomyces fumanus containing K15N18O3 as the sole source of nitrogen; the nitro group of dioxapyrrolomycin produced under these conditions contained the same ratio of 18O to 15N as was present in the labelled nitrate precursor, the extent of 18O enrichment of the nitro group being determined by negative electron impact mass spectrometry and 15N n.m.r. spectroscopy.

T. S. Dunne

Papers

Calichemicins, a novel family of antitumor antibiotics. 2. Chemistry and structure of calichemicin .gamma.1I

Calicheamicins, a novel family of antitumor antibiotics. 4. Structure elucidation of calicheamicins .beta.1Br, .gamma.1Br, .alpha.2I, .alpha.3I, .beta.1I, .gamma.1I, and .delta.1I

(Malonato)bis[sulfinylbis[methane]-S]platinum(II) compounds: versatile synthons for a new general synthesis of antitumor symmetrical and dissymmetrical (malonato)platinum(II) complexes

Water-soluble third generation antitumor platinum complexes, [2,2-bis(aminomethyl)-1,3-propanediol-N,N']-[1,1-cyclobutanedicarboxylato(2-)-O,O']platinum(II) and [1,1-cyclobutanedicarboxylato(2-)-O,O'][tetrahydro-4H-pyran-4,4-dimethanamine-N,N']platinum(II)

Direct biochemical nitration in the biosynthesis of dioxapyrrolomycin. A unique mechanism for the introduction of nitro groups in microbial products