Michael C. Venuti

A Regio- and stereocontrolled total synthesis of (-)-indolactam-V

Abstract (-)-Indolactam-V (IL-V) ( 1 ) -was prepared in 10 steps from L-tryptophan methyl ester in 17.1% overall yield. The key steps involve regiospecific thallation of the acylindole intermediate ( 4 ), followed by azide displacement and reduction to introduce the 13-amino group. Control of the C-ll stereocenter was achieved by S N 2 displacement of the chiral inflate ( 10 ), derived from D-valine. The thallium mediated closure of dipeptide ( 17 ) did not provide an alternative route to IL-V.

Chapter 20. Platelet-Activating Factor: Multifaceted Biochemical and Physiological Mediator

Publisher Summary This chapter discusses the characteristics and the role of platelet-activating factor (PAF) as a multifaceted biochemical and physiological mediator. Procedures for both semi-synthesis and total synthesis of PAF on a sufficiently large scale for biochemical investigations have been refined and improved. Reported successes in the search for specific receptor antagonists of PAF action can be divided into two categories. The first group is comprised of lipids possessing a thiazolium polar head group. A second group is comprised of two natural products, kadsurenone and ginkgolide-B, structurally unrelated to PAF. Detailed examination of the release of PAF from a variety of cell types, utilizing a number of stimuli, has provided new information regarding the two biosynthetic pathways for the production of PAF. The most recent development in PAF biosynthesis has provided a surprising link between PAF itself and the arachidonate metabolites. The structural requirements for and the existence of antagonists of the PAF activity both directly point to the presence of specific PAF cell membrane receptors in platelets. Although PAF is a potent platelet-aggregating agent, detailed investigations of the pathophysiological manifestations of the effects of PAF have focused attention on its role as a key anaphylactomimetic mediator. The hypotensive activity of PAF, one of the first noted and the most pronounced pharmacological property, observable in the rat, whose platelets are refractory to PAF. The still expanding range of biological activities, exhibited by PAF, coupled with the variety of cell types that produce PAF, firmly established it as a key mediator of the inflammatory and anaphylactic events. While it is unlikely that PAF itself is solely responsible for the pathogenesis of acute and allergic inflammation, it is quite apparent that PAF must be included among the important mediators of normal and abnormal acute allergic and inflammatory reactions.

Chapter 31. The Impact of Biotechnology on Drug Discovery

Publisher Summary The evolution of recombinant DNA technology, from scientific innovation to pharmaceutical discovery process, has occurred in parallel with the development of contemporary medicinal chemistry. The products of biotechnology research, many of which satisfy the previously unfulfilled markets, share few of the traits characteristic of traditional pharmaceuticals. Biotechnologically derived therapeutics are large extracellular proteins destined to be, with few exceptions, injectibles for use in either chronic replacement therapies or in acute or near-term chronic situations for the treatment of life-threatening indications. The prospects for uncovering the molecular etiology of a disease state or for gaining access to a disease-relevant target enzyme or receptor are already being realized. In addition, the possibility of rationally intervening in disease states at other points is becoming more evident. Regulation of inducible or tissue-specific gene expression may become an important method for pharmacological intervention. The tools to monitor such events are only now becoming available, as in the case of the low-density lipoprotein receptor, where tissue-specific upregulation of receptor population may successfully compete with other cholesterol-lowering agents.

Chapter 20 Dermatological Agents

Publisher Summary The field of dermatology encompasses biology, pharmacology, and pathophysiology, and is aimed at the development of more sophisticated and more effective therapies for diseases of the skin. This chapter discusses the previous review in this series, focusing on the newly developed treatments for acne, psoriasis, acute skin inflammation, and alopecia. The generally accepted model of acne development involves enhanced sebum excretion under androgen control, hypercornification of the sebaceous duct, and its subsequent colonization with P. acnes and eventual production of inflammation by chemotactic factors secreted by P. acnes . Most mild to moderate cases of acne can be held in check and eventually cleared by the use of topical benzoyl peroxide or either orally or topically administered antibiotics. In contrast to the advances in acne, treatment of psoriasis remains palliative, providing only temporary remission to this oftentimes physically and emotionally debilitating disease. Steroids remain the first line of topical treatment in acute skin inflammation almost regardless of the cause, and despite their well-known side effects of dermal atrophy and adrenal-pituitary suppression upon systemic absorption. Alopecia areata , a non-scarring localized and often sudden hair loss, has been treated in recent years with contact allergens, but this therapy is viewed as too radical for routine use. Chance observation of the dermatological side effects of various drugs, coupled with fundamental advances in the understanding of the complex biochemical pathways that cause or are caused by altered dermal metabolism, have pointed way to cost effective and cosmetically acceptable regimens conducive to patient compliance. These agents, ideally possessing both high efficacy and low toxicity, is likely to provide the urgently needed therapies for diseases of the skin for which only palliative treatment is currently available.

Chapter 20. Therapeutic Approaches to Rheumatoid Arthritis and Other Autoimmune Diseases

Publisher Summary The immune-based chronic inflammation, triggered by persistent bacterial, viral or autoantigens, or by an aberration in cytokine regulation of T-cells, forms the underlying pathophysiology of rheumatoid arthritis (RA) and other autoimmune diseases, such as systemic lupus erythematosus (SLB), psoriasis and psoriatic arthritis, atopic dermatitis, ankylosing spondlitis (AS), and chronic inflammatory bowel disease. To slow or halt tissue destruction, and more specifically joint damage, agents now classified as disease-modifying antirheumatic drugs (DMARDs), such as gold, D-penicillamine (DPA) and the antimalarials, while not necessarily providing a cure, do retard the progress of the underlying disease in a less than predictable manner by mechanisms as yet only poorly understood. This chapter highlights some recent DMARD candidates. Sulfasalazine, useful in the treatment of ulcerative colitis, has been evaluated against other DMARDs in a number of RA studies, which indicate that long-term sulfasalazine treatment of RA is a viable option, especially in patients resistant to gold or DPA. Another DMARD candidate, thalidomide, previously used as a sedative, hypnotic and antiemetic until withdrawal because of its severe teratological side effects, showed therapeutic utility in a form of leprosy, discovered while a patient received it as a sedative. The chapter discusses immunomodulatory drug therapy—perturbation of the delicate balance in the cellular and humoral immunoregulatory network results in a net expression of aberrant hyperreactivity in most autoimmune diseases. Thus, although immunosuppression might seem warranted for diseases of chronic inflammation and immunologic hyper-reactivity, immunomodulation (immunoregulation), the dampening of hyperactive responses or enhancing defective negative influences, particularly through manipulation of the soluble mediators interleukins is the required therapeutic strategy. The chapter considers the properties of NSAIDs as immunomodulatorv DMARDs, antioxidants and peroxvnenase inhibitors, phospholipase and phosphodiesterase inhibitors, and inhibition of complement.

Synthesis and biological activity of a 5,6-substituted teleocidin

Abstract The synthesis of 5,6-substituted teleocidin analogue 3 is reported. Reduction of oxime 7 (obtained from indole 6 ) gave diastereomeric amines 8 and 9 which were cyclized to give esters 10 and 11 , respectively. Reduction of 10 yielded teleocidin analogue 3 , which displayed activity comparable to (−)-indolactam V in a standard 3 [H]-phorbol-dibutyrate binding assay.