Quinone antitumor antibiotics

Quinone antitumor antibiotics, synthetic studies of 88YGK801. Synthetic studies toward CC-1065, PDE-I, and PDE-II 87H(25)701. 

Angle, S. R. Rainer, J. D. Woytowicz, C. Synthesis and chemistry of quinone methide models for the anthracycline antitumor antibiotic. J. Org. Chem. 1997, 62, 5884-5892. 

Anthracyclines are antitumor quinone containing antibiotics produced by different strains of Streptomyces. Some of them, such as adriamycin doxorubicin), and daunorubicin are broad spectrum antitumor compounds. They act by binding to DNA and interfering with DNA replication and gene transcription. Their limitations for clinical use are cardiac toxicity and drug resistance phenomena. Consequently, intense structure-activity relationship studies have been performed to improve the pharmacological profile as well as to enhance the affinity for DNA. In particular, a number of fluorinated anthracyclines have been prepared with introduction of fluorine atoms into D or A cycles, and into the aglycone side chain linked atC-14. ... 

Stripping voltammetry has recently received a great deal of interest due to its high sensitivity and rapid direct assay (see Sec. III.F). Examples using stripping voltammetry for the trace-level determination have included assays for penicillins [121], diltiazem (calcium channel blocker) [122], mitomycin C (quinone-containing antitumor antibiotic) [123], captopril (hypotensive drug)... 

Mitomycin C, 1, is a potent antitumor antibiotic discovered by Japanese scientists in fermentation cultures of Streptomyces caespitosus. It has been described as "small, fast and deadly (but very selective)" and has an extraordinary ability to crosslink the complementary strands of the DNA double helix with high efficiency and absolute specificity. It is so lethal that one crosslink per genome is sufficient to cause death of a bacterial cell. Mitomycin C, which is widely used clinically as an antitumor drug, does not react with DNA, but enzymatic reduction of the quinone induces a cascade of transformations which results, ultimately, in formation of the DNA crosslink 2. 

Quinone diazides such as (104) are readily prepared by nitrosation of 4-aminophenols. On photolysis, (104) smoothly cyclizes to (105), a model for the antitumor antibiotic CC-1065 (equation 43). ... 

General name for antitumor antibiotics with benzo-quinone and aziridine structural units from cultures of streptomycetes (e. g., Streptomyces lavendulae, S. ver-ticillatus, S. caespitosus). There are more than 15 natural variants containing a pyrrolo) 1,2-a)indole system and differing in R and R, with OH in place of OCHj at C-9a, and different stereochemistries at C-9. The violet to blue-violet, optically active M. crystallize readily and are soluble in water, methanol, and acetone. A cluster of 47 bacterial genes that control biosynthesis of M. C has been characterised. The biosynthetic building block of the benzoquinone (C7N) unit is 3-amino-5-hydroxybenzoic acid, several total syntheses have been repotted. 

It is well known that anthracycline antibiotics having an anthra-quinone group in the molecule are an important class of widely used antitumor antibiotics. Their clinical efficacy is limited by severe dose-related cardiotoxicity 2 It j s been considered that these undesirable side effects as well as the clinical benefits result from their ability to shuttle electrons from NADPH-cytochrome P-450 reductase to molecular oxygen that is, in turn, transformed into activated oxygen species such as superoxide anion radical, hydroxyl radical, and hydrogen peroxide - activated oxygen species have been proposed to play a fatal role in DNA scission and peroxidation of mitochondrial membranes . However, the detailed mechanism is not yet fully understood. 

Podophyllotoxin 3 is a naturally occurring antitumor antibiotic . Attempts to reduce the toxicity have resulted in the synthesis of glucosidic phenolic derivatives, VP-16 (etoposide, a semisynthetic analog) 4a and VM-26 (teniposide) 4b. Their mode of action is thought to be associated with DNA breakage . Haim et al. proposed a mechanistic pathway entailing oxidation with subsequent 0-demethylation to form the o-quinone metabolite 5a (Equation 2). In vivo conversion of methoxyl to hydroxyl has been previously observed . Electrochemical oxidation of VP-16 and other methoxyphenols also leads to quinone products. 

The antitumor antibiotic quinones and their model analogues display favorable reduction potentials . Evidence suggests that quinone 5a is the species responsible for the bioactivity. Thus, the phenolic hydroxyl group is crucial, and metabolic activation is necessary for induction of strand breaks . In another study, free radical scavengers such as DMSO, thiourea, and disulfiram inhibited the cleavage of DNA by 4a . More... 

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... 

Mushrooms and various fungi and lichens are rich in enol metabolites and many exhibit significant bioactivities , such as usnic acid (14) which serves as a regulator for plant growth and shows antitumor and antibiotic activities " . The widely distributed quinone polyporic acid (15a, PPA) from the Purple-Dye Polypore mushroom (Hapalopilus nidu-lans) and other sources is a weak inhibitor (IC50 = 0.1 to >1.5 mM " ) of dihydroorotate... 

Nanaomycin A (128), an antibiotic pyranonaphthoquinone, has been synthesized via this route starting from (127). This method has also been applied to the synthesis of royleanone (129), an abietanoid diteipene quinone possessing antitumor cytotoxicity, in which the highly substituted quinone skeleton has been efficiently constmcted by using the maleoylcobalt complex. ... 

To date, only two purely NRPS biosynthetic machineries have been reported from myxobacteria. The first NRPS pathway to be characterized (and the first myxobacterial gene cluster to be identified) directs the biosynthesis of the DNA-binding antibiotic and antitumor agent saframycin Mxl 30 in M. xanthus Its heterocyclic quinone structure originates from a linear peptide intermediate 27 (Ala-Gly-Tyr-Tyr), which is synthesized by a tetramodular assembly line composed of two multifunctional NRPSs, SafA and SafB (Figure 10). It is likely that the tyrosine precursor is modified to 3-hydroxy-5-methyl-0-methyltyrosine through hydroxylation as well as O- and C-methylation reactions, before the monomer is loaded onto the NRPS complex. Once the tetrapeptide structure (27) is constructed, chain release by the last module of the assembly line should occur. However, in SafA, the typical C-terminal TE domain is substituted with a putative... 

---