Acetylenes cytotoxicity

Inhibition of JH III biosynthesis In vitro. All three acetylenic compounds were significantly better Inhibitors of JH biosynthesis than precocene II under similar Incubation conditions (Fig. 4). Compound 2 was the best Inhibitor tested here, with an I50 of 16 pM, more than 25 times better than precocene II. Whether this better performance as an Inhibitor Is due to a closer structural analogy with the natural substrate of the epoxidase or whether it Is a consequence of the presumed difference In the mode of action (Irreversible Inhibition of the epoxidase for cytotoxicity of precocene epoxide eventually resulting In decreased JH biosynthetic rate for 1) Is not presently known. The Insecticide synergist (4) proved to be about 7 times better than precocene II. Its activity as an inhibitor of JH biosynthesis by D. punctata CA is similar to that of 3 and the methylenedioxyphenyl analog of JH (Ro 20-3600). 

Clinical development is hampered due to the extremely scarce supply of discodermolide from the natural source. Thus, total synthesis provides the only viable route to useful quantities of this novel cytotoxic polyketide. Consequently, there have been considerable synthetic efforts toward the total synthesis of discodermolide [16], Up to date, five total synthesis of (+)- and/or (-)-discodermolide have been reported, one by Schreiber [3], one by Smith [17], one by Myles [18], one by Marshall [19] and one by Paterson [20]. All the syntheses are convergent. Schreiber and Myles employed an analogous connection by using a Nozaki-Kishi addition of a C8 acetylenic or (Z)-vinylic chromium to a C7 aldehyde for the major... 

For other acetylenic compounds, we have isolated nepheliosyne A (99) [56], a new C47 acetylenic acid, from the sponge Xestospongia sp., collected off Kerama Islands, which also contained three cytotoxic and... 

Dicobalt-hexacarbonyl-alkyne complexes are another class of organometallic compounds with good stability imder physiological conditions. Complexation of the alkyne proceeds smoothly under mild conditions by reaction with Co2(CO)g imder loss of two molecules of CO [79]. The applicability of this reaction to peptides was shown by Jaouen and coworkers by the reaction of Co2(CO)g with protected 2-amino-4-hexynoic acid (Aha) and dipeptides thereof (Boc-Phe-Aha-OMe and Ac-Aha-Phe-OMe) [80]. Similarly, Cp2Mo2(CO)4 complexes of these alkynes were obtained. It has been shown that the C-terminal Met" in SP can be replaced by isostere analogs without appreciable loss of physiological activity. The same is true for the C-terminal Met in neurokinin A (NKA), another tachykinin peptide hormone (Scheme 5.16). Alkyne analogs of SP and NKA were obtained by replacement of these methionines with norleucine acetylene residues. Alternatively, Lys in NKA may be replaced by an alkyne derivative which can also be complexed to Co2(CO)g as shown in Scheme 5.16. Complexation with Co2(CO)g proceeds smoothly in about 50% yield for all derivatives [81]. After HPLC purification, these cobalt alkyne peptides were comprehensively characterized spectroscopically. Most notably, they exhibit typical IR absorptions for the metal carbonyl moieties between 2000-2100 cm [3]. Recently, there is renewed interest in Co2(CO)5(alkyne) complexes because of their cytotoxicity [82-84]. 

Hudson, J.B., E.A. Graham, N. Miki, G.H.N. Towers, L.L. Hudson, R. Rossi, A. Carpita, and D. Neri (1989) Photoactive Antiviral and Cytotoxic Activities of Synthetic Thiophenes and Their Acetylenic Derivatives. Chemosphere 18,2317 (1989). 

The acetylenes and linear furanocoumarins (psoralens) are examples of bioactive secondary metabolites that have been considered undesirable in plant foods due to their toxic effects. Some acetylenes are known to be potent skin sensitizers and irritants, and neurotoxic in high concentrations, but have also been shown to have a pronounced selective cytotoxic activity against various cancer cells. Due to their role in plant defence many acetylenes and psoralens are considered natural pesticides or in some cases phytoalexins since their formation is often induced in plants as a response to external stimuh. Psoralens are photoactivated secondary metabolites that have been used since ancient times to treat human skin disorders. However, the use of these furanocoumarins in medicine has been associated with increased incidence of skin cancer, and a number of studies have also demonstrated that the furanocoumarins can be carcinogenic, mutagenic, photodermatitic and to have reproductive toxicity. 

Figure 5.12 The possible reaction of falcarinol with biomolecules, which may explain its interaction with the immune system leading to allergenic reactions (type IV). The bioactivity of acetylenes of the falcarinol-type, in particular their cytotoxic activity, may be explained by a similar mechanism. RSH = thiol residue of a biomolecule, for example, a protein.

Figure 5.13 Examples of highly cytotoxic acetylenes of the falcarinol-type isolated from medicinal plants.

As falcarinol, falcarindiol and related Ciy-acetylenes are common in the Arahaceae and Apiaceae one might expect that more species within these families exhibit cytotoxic activity, including food plants. The strong selective cytotoxic activity of falcarinol and related Ci7-acetylenes towards different cancer cells indicates that they may be valuable in the treatment or prevention of different types of cancer and could contribute to the health promoting properties of food plants that contain these compounds. Also the cytotoxic activity of dehydrofalcarinol and dehydrofalcarindiol are interesting, since these compounds are widely distributed in several tribes of the Asteraceae (Bohlmann et al 1973 Christensen 1992). So far only dehydrofalcarindiol has been isolated from tarragon (Table 5.1), but they may be present in other food plants of this family, and hence may contribute to the health promoting properties of some members of the Asteraceae. 

Due to the high cytotoxicity of Cu(I) ion and the difficulty in completely removing it after the CuAAC reaction, it becomes highly desirable to promote the [2-1-3] cycloaddition between the acetylene and the azide under Cu ion-free conditions. In this coimection, Kiser reported the in situ preparation of cross-linked hydrogels by using a Cu(I)-free Huisgen cycloaddition between an azide-functionalized methacrylate polymer 37 and an activated diacetylene 38 (Scheme 11) [51]. However, even with 38 as the activated dipolarophile, the rate of cross-linking was still too slow (10% completion in 49 h at 24°C) to be useful in most in situ applications. 

From Lyn ya majuscida collected at Pulau Hantu Besar, Singapore, the cytotoxic hantupeptins A-C also contain the three hydroxyacids Hmoya, Hmoea, and Hmoaa (Tripathi et cd., 2010a). The acetylenic acid Hmoya is also present in onchidin B, a cyclodepsipeptide isolated from the mollusk Onchidium sp. (see Chapter 23). 

Watanabe, K., Tsuda, Y, Yamane, Y, Takahashi, H., Iguchi, K., Naoki, H., Fujita, T, and Van Soest, R.W.M. (2000b) Strongylodiols A, B, and C, new cytotoxic acetylenic alcohols isolated from the Okinawan sponge of the genus Strongylophora as each enantiomeric mixture with a dififerent ratio. Tetrahedron Lett., 41, 9271-9276. 

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