Adriamycin synthesis

The antineoplastic antibiotics, unlike their anti-infection antibiotic relatives, do not have anti-infective (against infection) abilily. Their action is similar to the alkylating dragp. Antineoplastic antibiotics appear to interfere with DNA and RNA synthesis and therefore delay or inhibit cell division, including the reproducing ability of malignant cells. Examples of antineoplastic antibiotics include bleomycin (Blenoxane), doxorubicin (Adriamycin), and plicamycin (Mithracin). 

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). 

Since the enzymes involved in PS synthesis are located in ER or MAM, and PSD is exclusively located at the inner mitochondrial membrane, the conversion of PS to PE by PSD has been used as an indicator of PS translocation into the inner mitochondrial membrane (Dennis and Kennedy, 1972 Voelker, 1990). Recent studies have shown that the transport of newly synthesized PS to the outer mitochondrial membrane requires no cytosolic proteins and is probably mediated by direct contact region between MAM and mitochondria (Voelker, 1989 Voelker, 1993 Shiano et al., 1995). It is also suggested that the translocation of PS from the outer to iimer mitochondrial membrane occurs through the contact sites where the two mitochondrial membranes are closely apposed and linked in a stable manner, since agents that dismpt the contact sites such as 1,4-dinitrophenol and adriamycin inhibit the PS transport (Hovius et al., 1992 Voelker, 1991). 

We have shown that polymeric micelles constmcted of block copolymers of poly(ethylene oxide) (PEG) and poly(L-asparate) containing the anticancer dmg (adriamycin, ADR) selectively accumulate at solid tumor sites by a passive targeting mechanism. This is likely due to the hydrophilicity of the outer PEG chains and micellar size (<100 nm) that allow selective tissue interactions [17,18]. Polymeric micelle size ranges are tailored during polymer synthesis steps. Carefully selection of block polymer chemistry and block lengths can produce micelles that inhibit nonselective scavenging by the reticuloendothelial system (RES) and can be utilized as targetable dmg... 

Perhaps a bit more subtle than those agents that react chemically with DNA are those that insert themselves between the stacked bases of the DNA double helix— intercalation. This alters the regular structure of the DNA molecule and may lead, for instance, to inhibition of mRNA synthesis. The structures of the intercalcating agents are generally quite complex and I will spare you the complexity. However, three names may be familiar—dactinomycin (Actinomycin D), daunorubicin (daunomycin), and doxorubicin (Adriamycin)— and intercalation is how they work. All three are natural products and were isolated from the fermentation broths of Streptomyces species. 

The synthesis proceeds from 37 through the intermediacy of 43 and 44. The glycoside derived from 45 and adriamycinone shows antitumor activity similar to that of the isomer adriamycin, but exhibits a much faster cellular uptake (1 ). Also, the an alternative to based on regioselective double-bond functionalization ( ). Thus, methyl 2,3,6-trideoxv-Q-L-threo-hex-2-enopyranoside (46), a key intermediate in the aforementioned procedure, is obtained from 11 upon reaction with Ph P=CHCHOCH CH, followed by controlled methanolysis. 

An example of the synthesis of an adriamycin-dextran-antibody (anticarcino-embryonic mAb) is shown in Fig. 9 [54]. The synthetic design called for the modification of all three components, i.e., drug, polymeric carrier, and antibody before conjugation. 

Fig. 9. Synthesis of a targetable dextran-adriamycin conjugate. Note that amino groups were introduced into the dextran structure, whereas the amino group of adriamycin was converted into a carboxylic group. According to [54]...

Synthesis of an adriamycin-HPMA copolymer-galactosamine conjugate is shown in Fig. 10. Attachment/release points at the side-chain termini are created by incorporation of tailor-made comonomers into the copolymer structure. 

Fig. 10b. A scheme of its synthesis. First, a reactive comonomer. Af-methacryloylglycyl-phenylalanylleucylgycine p-nitrophenyl ester was synthesized. In the second step a polymeric precursor is prepared by copolymerization of the reactive comonomer with A-(2-hydroxyp-ropyl)methacrylamide. After purification and characterization of the polymeric precursor, the anticancer drug (adriamycin) and targeting moiety (galactosamine) are attached by consecutive aminolysis. For details see, e.g., [169]...

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. 

Cleavage of alkyl ary ethers (4, 305). The most difficult step in a recent synthesis of aklavinone (3) is demethylation of 1 to 2. Lewis acid reagents (BBr3) were useless because of preferential attack of the allylic hydroxyl nucleophilic demethylation (LiSCH3) results in concomitant aromatization of ring A. Demethylation "with Lil buffered with benzoic acid in pyridine-collidine at 145° was successful and proceeded in 92% yield.4, Aklavinone is the aglycone of an antitumor anthracycline that is less toxic than adriamycin. 

Yokoyama, M., T. Okano, Y. Sakurai, and K. Kataoka. 1994. Improved synthesis of adriamycin-conjugated poly(ethylene oxide)-poly(aspartic acid) block copolymer and formation of unimodal micellar structure with controlled amount of physically entrapped adriamydirControl. Rel.32 269-277. 

An improved total synthesis of the aglycone (180) of 11-deoxyadriamycin-type antibiotics, which show stronger antineoplastic activity and/or less car-diotoxicity than daunomycin and adriamycin, was accomplished by applying the method to dihydroxyacetone (180) from ethynylcarbinol (182), prepared by strong base-induced cycloaddition of the substituted tetrahydrohomophthalic anhydride (181) [137], using PIFA [78] (Scheme 46). 

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]... 

Ethynyl groups attached to various skeletons were generally oxidized to the hydroxyacetyl functionality. The reaction was useful in the synthesis of natural products and analogues with a dihydroxyacetone side chain, e.g. adriamycin and corticosteroids. Some examples are given in Table 4.1. 

The anthracyciinone class of anticancer compounds (which includes daunomycin and adriamycin) can be made using a mercury (I I )-promoted alkyne hydration. You saw the synthesis of alkynes in this class on Chapter 9 where we discussed additions of metallated alkynes to ketones. Here is the final step in a synthesis of the anticancer compound deoxydaunomycinone the alkyne is hydrated using Hg2+ in dilute sulfuric acid the sulfuric acid also catalyses the hydrolysis of the phenolic acetate to give the final product. 

Furthermore, the method can be applied to the synthesis of 4-demethoxyadriamy-cinone, which is the key structure of the anti-cancer drugs, the adriamycins such as idarubicin and aimamycin (52) (Eq. 3.69). The ruthenium-catalyzed oxidation of allyl acetate SO gives the corresponding a-hydroxyketone 51 in 60% yield (Eq. 3.69) [129]. 

Anthracycline antibiotics represented by daunomycin and adriamycin are weU known as anticancer agents and their reaction mechanisms with DNA have been extensively studied. However, an approach to understand the mechanism of drug action based on organic synthesis is still open. 

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