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

About: This article is published in Journal of the American Chemical Society.The article was published on 1987-05-01. It has received 471 citations till now.
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TL;DR: 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.
Abstract: 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.

1,264 citations

Journal ArticleDOI
15 Dec 2004-Nature
TL;DR: Improvements in approaches for natural-product isolation, characterization and synthesis could be opening the door to a new era in the investigation of natural products in academia and industry.
Abstract: 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.

1,016 citations

Journal ArticleDOI
TL;DR: 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 are described.
Abstract: 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.

749 citations

Journal ArticleDOI
TL;DR: What is known of the structure of the MRPs and the mechanisms by which they recognize and transport their diverse substrates are described and evidence that they may be involved in the clinical drug resistance of various forms of cancer is summarized.
Abstract: 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 ...

733 citations


Cites background from "Calichemicins, a novel family of an..."

  • ...The conjugate consists of an antibody targeted to CD33 that is conjugated via an acid-hydrolyzable linker to a derivative of the antitumor antibiotic calicheamicin- 1, which is released following internalization and entry into lysosomes (269)....

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Journal ArticleDOI
TL;DR: All reports of total syntheses that utilize arynes in ways that build complexity or introduce motifs essential to the completion of their targets are recounted.
Abstract: Within 14 years of the seminal experiments of J. D. Roberts leading to the first proposal of the structure of benzyne (1), synthetic organic chemists recognized the potential to exploit this highly reactive intermediate (and its substituted variants) in the total synthesis of natural products. More specifically, it was recognized that arynes offered the strategic advantage of rapidly functionalizing an aromatic ring by forming multiple carbon− carbon or carbon−heteroatom bonds in a single operation, often in a regioselective manner. Initially, the scope of synthetic applications was somewhat limited by the harsh conditions required to produce the aryne species. Many of these methods required strong bases, such as n-BuLi, or high temperatures (Scheme 1). However, with the development of milder methods for the generation of arynes came increased interest in employing them in the synthesis of more complex polycyclic systems. Most recently, the use of o-silyl aryl triflates as aryne precursors has allowed generation of the reactive intermediate under almost neutral conditions. To date, over 75 individual natural products have been prepared using arynes to generate key synthetic intermediates. Herein are recounted the reports of total syntheses that utilize arynes in ways that build complexity or introduce motifs essential to the completion of their targets. The methods by which the authors featured in this review accomplish this task reflect the versatility of arynes as reactive intermediates for synthesis (Scheme 2). For the purposes of organization, the syntheses are divided into subgroups on the basis of the type of aryne transformation: (i) nucleophilic additions or multicomponent reactions, (ii) σ-bond insertion reactions, (iii) [4 + 2]- and [2 + 2]-cycloaddition strategies, and (iv) metal-catalyzed aryne reactions.

660 citations