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Human TNF-a is initially synthesized as a 233 amino acid polypeptide that is anchored in the plasma membrane by a single membrane-spanning sequence. This TNF pro-peptide, which itself displays biological activity, is usually proteolytically processed by a specific extracellular metallo-protease. Proteolytic cleavage occurs between residues 76 (Ala) and 77 (Val), yielding the mature (soluble) 157 amino acid TNF-a polypeptide. Mature human TNF-a appears to be devoid of a carbohydrate component, and contains a single disulfide bond. 

Mature hGH contains 191 amino acid residues and displays a molecular mass of 22 kDa. It also contains two characteristic intrachain disulfide linkages. hGH mRNA can also undergo alternate splicing, yielding a shortened GH molecule (20 kDa), which appears to display biological activities indistinguishable from the 22 kDa species. 

Other heterocyclic N-oxides have been found to display biological activities that may depend on their proven or hypothesised ability to release NO these include 4/ /-pyrazol-4-oTie 1,2-dioxides 71, 2H-1,2,3-triazole 1-oxides 72, benzotetrazine 1,3-dioxides 73 and 1,2,3-benzotriazine 3-oxides 74. These systems have been less extensively studied than the furoxan and 1,2-diazetine dioxide systems discussed above. 

Filgrastim is a recombinant human G-CSF (produced in E. coli), approved for chemotherapy-induced neutropenia since 1991. Although the 18.8 kDa recombinant product is not glycosylated and contains an additional N-terminal methionine residue (due to expression in E. coli), it displays biological activity indistinguishable from native G-CSF. The product is presented in freeze-dried format and contains buffer elements as well as sorbitol and Tween as excipients. 

Figure 1.8 Chemical structures of derivatized 2-aminothiazoles displaying biological activities on numerous target proteins.

There is a growing interest in naturally occurring phenolic compounds that display biological antioxidant properties such as -hydroxycinnamic acid, ferulic zcid, caffeic acid/ and curcumin which are ubiquitous in plant food. It has been demonstrated that the interaction of the oxidizing OH adduct of DNA, poly-A and poly-G with hydrox-ycinnamic acid derivatives proceed via electron transfer. Cinnamic acid derivatives have been shown to be able to scavenge superoxide, peroxyl, and hydroxyl radicals. 

Some bithienyl and terthienyl derivatives display biological activities including antifungal, nematocidal, and seed germination inhibition. The Stille reaction is regarded as the method of choice for the preparation of these thiophenes. For example, the union of 5-iodo-2-thiophenecarboxaldehyde and 2-tributylstannylthiophene furnished 5-(2 -thienyl)-2-thiophenecarboxaldehyde (209) [96]. In addition, terthienyl and bithienyl derivatives have been synthesized using 3,4-dinitro-2,5-dibromothiophene [143] and... 

This mild procedure for the solid-phase synthesis of peptides containing sterically hindered residues can be easily extended to generate combinatorial libraries of unnatural peptides, which may display biological properties superior to those of natural counterparts. 

Bombesin family, a subfamily of the bombesin-like family to which belong bombesin, alytensin and gastrinreleasing peptide, a mammalian counterpart for bombesin. The amphibian peptides bombesin and alytensin are structurally very similar and display biological effects when applied to mammals, such as hypertensive action, stimulation of the uterus and digestive tract, hyperglycemic effect, stimulation on the gastric secretion and increase of insulin levels in peripheral blood. 

Relevance Technical applications (e.g., displays) Biological systems, membranes, Langmuir-Blodgett-films... 

The carbodiimide 2, in contrast to 1, displays biological effects in vitro that may be responsible for the activity in vivo. In particular, 2 is a potent inhibitor of mitochondrial ATP synthesis at the ATP synthase level in vitro [10,18] and in vivo [22-24]. Radiolabeling experiments with [ " Cj-2 confirm that it covalently binds to the 8-kDa proteolipid of Fo of the mitochondrial ATP synthase in isolated mitochondria from insect flight muscle and rat liver. Because binding is competitively blocked by DCCD and partly inhibited by venturicidin it has been concluded that 2 and the classical and well-studied inhibitor DCCD [25] share the same binding site on the Fo proteolipid [26]. 

The discovery of a natural product with a novel carbon skeleton will undoubtedly challenge organic chemists to develop synthetic routes for its construction. If the natural product is complex, because of the presence of delicate functional groups and/or myriad chiral centers, the challenge becomes virtually irresistible. If the material displays biological activity, organic chemists will succumb to the challenge, and in time, a synthesis will be achieved. 

Among various heterocycUc scaffolds which display biological activity, the A -tetrazoUne-5-one scaffold is an interesting candidate. Depending on the substitution pattern, A -tetrazoline-5-ones can serve either as substances for pest management or for medical purposes. 

Bisindoles, such as hamacanthin A, isolated from marine sponges Hamacantha sp., Spongosor-ites sp.), or the more famous indole-3-carbinol (I3C), a compoimd found in cruciferous vegetables (cabbage, kale, cauliflower, broccoli, Brussels sprouts) and its bisindole metabolite, 3,3 -diindolylmethane (DIM), have displayed biological activities such as antimicrobial, antiparasitic, anti-inflammatory, and anticancer and are high up on the interest list of many researchers [43]. 

FIGURE 30.1 The two quintessential cycloaromatization reactions, the Bergman and Myers-Saito cyclizations (top) and natural products that display biological activity based on these cyclizations (bottom). 

The existence of biologically active metabolites of retinoic acid has been reported. Krishnamurthy et al. (1963) detected a fat-soluble metabolite of retinoic acid, which displayed biological activity in a rat curative assay, in the liver of chicks administered a 10-mg oral dose of the parent retinoid. Similarly, Wolf et al. (1963) reported that an intestinal metabolite, isolated from retinoid-deficient rats injected with labeled retinoic acid, was active in restoring to normal levels the mucopolysaccharide biosynthesis in retinoid-deficient rat intestinal cell-free particle suspensions. The same laboratory also described a decarboxy-lated metabolite of both retinol and retinoic acid that was isolated from the intestine of retinoid-deficient rats administered retinol or retinoic acid. This compound, which appeared to have both carboxyl and hydroxyl functional groups, was biologically active in a growth assay (Yagishita et al., 1964). In... 

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