Antitumor agents/antibiotics

N. Uotani, H. Nakai, A. Terui, S. Yoshimatsu, Isolation and structural elucidation of new cyclotetrapeptides, trapoxins A and B, having detransformation activities as antitumor agents, /. Antibiot. 43 (1990) 1524. 

In seeking a synthetic route to an antibiotic antitumor agent, the Thiele-Winter synthon, with 2,3-bis(methoxycarbonyl)-l,4-ben2oquinone [77220-15-6] (60), was used to introduce a required third oxygen linkage (57). A 67% yield of (61) was obtained. 

Bleomycin and cyclosporine are the two economically most important streptomycete peptide antibiotics used as antitumor agents and immunomodulators, although dactinomycin is important medically for several tumors (see Chemotherapeutics, anticancer Immunotherapeutic agents). 

Echinomycin (131) has been shown to be an antitumor agent and to have antiviral and antibacterial properties. Its structure elucidation represents a triumph for and mass spectral studies (75JA2497). It has been demonstrated that echinomycin functions by inhibiting RNA synthesis in organisms such as Staphylococcus aureus. Echinomycin, levomycin and actinoleutin are members of the quinoxaline-peptide antibiotic family and all contain one or more quinoxaline rings (67MI21402). 

The mbromycins constitute an unusual structural class, due to the presence of the spiroketal moiety. A more typical example of a type II PKS-derived natural product is the antitumor agent hedamycin (Scheme 10.13) [39, 40]. Hedamycin belongs to a family of closely related compounds, the pluramycins. These antibiotics have the... 

Like the examples above, dihydroxyacetanilide epoxidase (DHAE) uses an olefin as the substrate for epoxidation. Its mechanism, however, is fundamentally different from those of cytochrome P450 or flavin-dependent enzymes. Dihydroxyacetanilide is an intermediate in the biosynthesis of the epoxyquinones LL-C10037a, an antitumor agent produced by the actinomycete Streptomyces LL-C10037 [75, 76], and MM14201, an antibiotic produced by Streptomyces MPP 3051 (Scheme 10.20) [77]. The main structural difference between the two antibiotics lies in the opposite stereochemistry of the oxirane ring. 

The tightly bound chromophore could be extracted from the protein with methanol [186], and the major component of the extract was determined to have the enediyne structure 116 (Figure 11.21), related to chromophores of other chromoprotein antitumor agents such as neocarzinostatin. Additional minor components were extracted, variously containing an OH group instead of OMe attached to the enediyne core, with Cl instead of OMe when chloride was present in the buffer salt, or with OEt instead of OMe when ethanol was used for the extraction. Another byproduct was isolated in the form of structure 117, consistent with a facile cy-doaromatization reaction as observed for all other enediyne antibiotics. Surprisingly, 117 also displayed antibiotic and antitumor activity, perhaps due to alkylation of DNA or protein by the aziridine. The interpretation of these results was that 116 and the other enediyne byproducts were merely artifacts of the extraction procedure and that the true structure of the maduropeptin chromophore is the aziridine 118. 

Quinone methides have been shown to be important intermediates in chemical synthesis,1 2 in lignin biosynthesis,3 and in the activity of antitumor and antibiotic agents.4 They react with many biologically relevant nucleophiles including alcohols,1 thiols,5-7 nucleic acids,8-10 proteins,6 11 and phosphodiesters.12 The reaction of nucleophiles with ortho- and /iara-quinone methides is pH dependent and can occur via either acid-catalyzed or uncatalyzed pathways.13-17 The electron transfer chemistry that is typical of the related quinones does not appear to play a role in the nucleophilic reactivity of QMs.18... 

The antibiotic sarkomycin (5), an antitumor agent, is a good target for synthetic efforts based on a Diels-Alder reaction. The retro synthesis of this compound is depicted in Scheme 5-3. 

Chatteijee et al., 1984 Sens et al., 1988), and cyclosporine (TrifiUis et al., 1984). Studies reported by Tay et al. (1988) in rabbit proximal tubule cultures with cisplatin revealed biochemical effects upon DNA synthetic activty that correlated with in vivo histochemical effects of this antitumor agent in animals. With respect to studies involving mercuric chloride and aminoglycoside antibiotics in primary renal cultures, light and electron microscopy revealed similar patterns of cellular pathology in vitro as compared to in vivo exposure in animals (Chatteijee et al., 1984 Aleo et al., 1987). 

Rebeccamycin is an antitumor or antibiotic agent isolated from bacteria " and contains a maleimide indolocarbazole framework. The Trp units in this molecule are chlorinated at the C-7 position and a flavin-dependent halogenase was identified as the enzyme that carries out this chlorination (Scheme 10). " There are many other halogenating enzymes known in the literature and these enzymes are responsible for the syntheses of metabolites containing bromine, chlorine, and fluorine. ... 

Rebeccamycin - antitumor and antibiotic agents (topoisomerase i inhibitor)... 

A and B, having detransformation activities as antitumor agents. Journal of Antibiotics (Tokyo), 43, 1524-1532. 

Parry and Wenying provided evidence for the pathway (shown in equation 5) for biosynthesis of the antibiotic and antitumor agent, valanimycin (5), in streptomyces by isolation and partial purification of an HA-forming enzyme. 

The alkylation products are synthetically useful because simple subsequent transformations furnishes precursors of important natural products as illustrated in Scheme 8E.23. Simple oxidative cleavage of allylic phthalimide 45 generates protected (5)-2-aminopimelic acid, whose dipeptide derivatives have shown antibiotic activity. The esterification via deracemization protocol is not limited to the use of bulky pivalic acid. The alkylation with sterically less hindered propionic acid also occurs with high enantioselectivity to give allylic ester 116, which has been utilized as an intermediate towards the antitumor agent phyllanthocin and the insect sex excitant periplanone. Dihydroxylation of the enantiopure allylic sulfone gives diol 117 with complete diastereoselectivity. Upon further transformation, the structurally versatile y-hydroxy-a,(f-un-saturated sulfone 118 is readily obtained enantiomerically pure. 

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