Adriamycin, analog

Benzocyclobutenediones are of interest on their own as well as for their usefulness as versatile intermediates. The synthesis of adriamycin analogs has been attempted and the syntheses of the similar tricyclic natural products islandicin 180 and digitopurpurone 181 (Scheme 45) are examples of this approach (77JOC2371). 

Horton D, Pnebe W. Nc v adriamycin analogs. Synthesis and antitumor activity of 14-sub-stituted 7 0(3,4 di 0-acetyl 2,6-dideoxy-a-L-lyxo-hexopyranosyl) daunomycinones. J Antibiot 1981 34 1019-1025. 

The medically useful products demethyltetracycline and doxorubicin (adriamycin) were discovered by simple mutation of the cultures producing tetracycline and daunorubicin (daunomycin), respectively. The tectmique of mutational biosynthesis (mutasynthesis) has been used for the discovery of many new aminoglycoside, macrolide, and anthracycline antibiotics. In this tectmique, a non-producing mutant ( idiotroph ) is isolated and then fed various analogs of the missing moiety. When such a procedure leads to a return of antibiotic activity, it usually is due to the... 

Kinder et al. (123,124) utilized a similar approach to the illudins, more specifically to illudin analogs such as 241 that retain efficacy against various cell lines, but are less toxic. The analog design involves a spirocyclopropyl cyclohexane that contains two electrophilic moieties (Scheme 4.63). Some of the analogs formed are as active as adriamycin against several human tumor cell lines. 

An alternative focus based on known antitumor activity of adriamycin-type systems stimulated the synthesis of the aza-anthraquinones 599 and 600 (Scheme 177) (84CC897). Thus, synergistic chloro-oxazoline directed metalation of 597 with methyllithium followed by treatment with 2,5-dimethoxybenzaldehyde and acid-promoted cyclization provided the lactone 598. Radical bromination and base-induced hydrolysis gave an intermediate keto acid which, upon Friedel-Crafts cyclization with methanesulfonic acid, led to the aza-anthraquinone 599 in modest yield. The azanaphthacene dione 600 was prepared by an analogous series of reactions starting with 597. 

A useful direct transformation of ethynylcarbinols (104) into dihydroxyacetones (105) was developed by Kita and co-workers [77, 78] and was utilized for the syntheses of anticancer agents, adriamycin (106) analogs, and antiinflammatory drugs, corticosteroids [Eq. (24)]. 

Daunomycin and its analog adriamycin are in clinical use as potent antitumor agents in combination chemotherapy against acute lymphocytic leukemia. It has been suggested that the antitumor properties are associated with intercalation of the anthracycline ring of the antibiotic into the DNA of rapidly proliferating neoplastic cells and subsequent blocking of RNA synthesis (72-75). [5]... 

Doxorubicin [dox oh ROO bi sin] and daunorubicin [daw noe ROO bi sin] are classified as anthracycline antibiotics. Doxorubicin, often referred to by its trade name adriamycin, is the hydroxylated analog of daunorubicin. Idarubicin, the 4-demethoxy analog of daunorubicin is also available. 

The phenothiazines, such as chlorpromazine, used in the treatment of schizophrenia, the tricyclic antidepressant drugs such as imipramine and amitryp-tUine, antimalarials such as quinacrine, and the anticancer agent adriamycin are structural analogs of riboflavin (see Figure 7.6) and inhibit flavokinase. In experimental animals, administration of these drugs at doses equivalent to those used clinically results in an increase in the EGR activation coefficient (Section 7.5.2) and increased urinary excretion of riboflavin, with reduced tissue concentrations of riboflavin phosphate and FAD, despite feeding diets providing more riboflavin than is needed to meet requirements (Pinto et al., 1981). 

Figure 7.6. Drugs that are structural analogs of riboflavin and may cause deficiency. Relative molecular masses (Mr) riboflavin, 376.4 quinacrine, 472.9 (dihydrochloride) chlorpromazine, 318.9 imipramine, 280.4 amitryptyline, 277.4 and adriamycin (doxorubicin), 543.5.

---