DNA cleaving

Bleomycin sulfate is used alone or in combination with other antineoplastic dmgs. Using this DNA-cleaving dmg, disease-free (possibly cured) survivors of some cancers have been seen, especially with the use of bleomycin in multidmg regimens. General reviews of bleomycin (234,242—245) and its mechanism of action (246—249) are available. 

Enediynes with ethylene carbonate fragment in the synthesis of dienediyne models of the biradical-forming and DNA-cleaving natural neocarzinostatin chromophore 99SL657. 

In the presence of Cu (II), the bithiazole (70) is a simple DNA cleaving agent, the first example of a 4,4 -bithiazole having this property <96CPB1761>. 

Bhattacharyya SP, Rao VB (1993) A novel terminase activity associated with the DNA packaging protein gpl7 of bacteriophage T4. Virology 196 34 4 Bhattacharyya SP, Rao VB (1994) Stmctural analysis of DNA cleaved in vivo by bacteriophage T4 terminase. Gene 146 67-72... 

The overall process from 3 gives straightforward access to ot-spirocyclop-ropyl heterocyclic ketones 310 [80], some of which display interesting DNA cleaving activity [80c]. The reaction conditions can be properly controlled in order to isolate the primary adducts 314-320 (Table 25). The cycloaddition to methoxycarbonyl substituted bicyclopropylidene 311 with 256 gave a mixture of the four possible regioisomeric and stereoisomeric anti-adducts 320 (see later) (entry 7). 

A more complex structure is that of leinamycin 45 (Scheme 15), a material with potent cytotoxic and antitumor properties, isolated from a Streptomyces sp. A 1,2 dithiolane-3-one ring is spiro fused to a complex macrolactam96 (and references therein). Leinamycin has the remarkable ability to cleave DNA. In brief, leinamycin reacts with a thiol and, after a profound rearrangement, forms an episulfonium ion. This ion alkylates the N7 position of guanosine residues in double stranded DNA an unstable adduct is depurinated by hydrolysis of the glycosidic bond between the alkylated base and a deoxyribose residue. Some structurally less complex l,2-dithiolane-3-one 1-oxides have a similar DNA cleaving ability.97... 

While enediyne natural products are efficient DNA cleaving agents, synthetic enediynes have been utilized widely to study the mechanistic details and obtain more efficient DNA cleavage activity. Simple enediynes (Fig. 8), with no binding units, show DNA cleavage albeit at very high concentra-... 

Fig. 9 Generation of DNA-cleaving diradicals from 4-alkynyl-3-methoxy-4-hydroxycyclo-butenones...

For the generation of DNA-cleaving moieties from 9-diazofluorenes two other mechanisms, which may not be relevant under physiological conditions, can be envisioned ... 

Since the double bond between C5 and C6 of the enynecumulene 169 is not required for the Myers-Saito cyclization, a large number of enyneallenes have been synthesized as model compounds for the neocarzinostatin chromophore and tested for DNA-cleaving activity in recent years, with the results having already been summarized extensively (cf. Chapter 20) [162]. 

A nucleophilic attack on the acetylenic ketone functionality of golfomycin A (184) was proposed as a potential pathway to form the benzannulated enyne-allene 185 (Scheme 20.38) [71]. Subsequent biradical formation has been postulated as a possible mechanism to account for its DNA-cleaving properties and antitumor activity. 

Yamakoshi YN, Yagami T, Sueyoshi S, Miyata N (1996) Acridine Adduct of [60]Fullerene with Enhanced DNA-Cleaving Activity. J Org Chem 61 7236-7237. 

Keywords Nucleosome, Chromosome, Intercalators, Groove-binders, DNA-cleaving agents. 

Gemtuzumab ozogamicin (30 Mylotarg ) Calicheamicin (31) Enediyne-type antibiotic NP-derived Microbial Anticancer DNA-cleaving 319-331... 

This reaction has recently been applied for the preparation of aza-analogs with the basic skeleton and functional groups of the extremely cytotoxic sesquiterpenes illudin (208) and ptaquiloside (209) [139]. Compounds 212-215 were successfully prepared by heating bicyclopropylidene (1) with the enantiomeri-cally pure nitrones 210,211 (Scheme 47) [138]. Some of these simple aza-analogs have indeed been found to exhibit DNA-cleaving abilities [138b,c]. 

Wender PA, Zercher CK, Beckham S, Haubold EM (1993) A photochemically triggered DNA-cleaving agent - synthesis, mechanistic and DNA cleavage studies on a new analog of the antitumor antibiotic dynemicin. J Org Chem 58 5867-5869... 

A further use of the system is to mediate the reaction of adamantane with carbon monoxide and oxygen to form 1-adamantanecarboxylic acid . When long-wavelength light (>300 nm) is used, hydroperoxides efficiently generate hydroxyl radicals without the use of metal ions and would be an extremely useful source of hydroxyl radicals, particularly in the design of DNA-cleaving molecules . ... 

Heavier metal ions and metal complexes can find sites on nitrogen atoms of the nucleic acid bases. Examples are the platinum complex cisplatin and the DNA-cleaving antibiotic neocarzinostatin (Box 5-B). Can metals interact with the n electrons of stacked DNA bases A surprising result has been reported for intercalating complexes of ruthenium (Ru) and rhodium (Rh). Apparent transfer of electrons between Ru (II) and Rh (III) over distances in excess of 4.0 nm, presumably through the stacked bases, has been observed,181 as has electron transfer from other ions.181a Stacked bases are apparently semiconductors.182... 

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