Anthracycline Antibiotics

Doxorubicin (adriamycin) (Figure 3.56) is produced by cultures of Streptomyces peucetius var caesius and is one of the most successful and widely used antitumour drugs. The organism is a variant of S. peucetius, a producer of daunorubicin (see below), in which mutagen treatment resulted in expression of a latent hydroxylase enzyme and thus synthesis of doxorubicin by 14-hydroxylation of daunorubicin. Doxorubicin has one of the largest spectra of antitumour activity shown by antitumour drugs and is used to treat acute leukaemias, lymphomas, and a variety of solid tumours. It is administered by intravenous injection and largely excreted in the bile. It inhibits the synthesis of RNA copies of DNA by intercalation of the planar molecule between base pairs on the DNA helix. The sugar unit provides further binding strength and also plays a major role in sequence-recognition for the binding. Doxorubicin also exerts some of its cytotoxic effects by inhibition of the enzyme topoisomerase II, which is responsible for cleaving and resealing of double-stranded DNA during replication (see page 137). Common toxic effects include nausea and vomiting, bone marrow suppression, hair loss, and local tissue necrosis, with cardiotoxicity at higher dosage. Daunorubicin (Figure 3.56) is produced by Streptomyces coeruleorubidus and S. peucetius,

CO2Me

CO2Me

aklavinone

I NMe, nOH

aklavinone

I NMe, rhodosamine r' L-2-deoxyfucose I OH 1

L-cinerulose O

OH O HN

idarubicin

OH O HN

OH O HN

mitoxantrone (mitozantrone)

Figure 3.57

OH O HN

OH HO

idarubicin

J,—■ "■■—../ aclacinomycin A O (aclarubicin)

mitoxantrone (mitozantrone)

Figure 3.57

and, though similar to doxorubicin in its biological and chemical properties, it is no longer used therapeutically to any extent. It has a much less favourable therapeutic index than doxorubicin, and the markedly different effectiveness as an antitumour drug is not fully understood, though differences in metabolic degradation may be responsible. Epirubicin (Figure 3.56), the 4 -epimer of doxorubicin, is particularly effective in the treatment of breast cancer, producing lower side-effects than doxorubicin. The antileukaemics aclarubicin from Streptomyces galilaeus, a complex glycoside of aklavinone (Figure 3.56), and the semi-synthetic idarubicin are shown in Figure 3.57. These compounds are structurally related to doxorubicin but can show increased activity with less cardiotoxicity. The principal disadvantage of all of these agents is their severe cardiotoxicity which arises through inhibition of cardiac Na+,K+-ATPase.

Mitoxantrone (mitozantrone) (Figure 3.57) is a synthetic analogue of the anthracyclinones in which the non-aromatic ring and the aminosugar have both been replaced with aminoalkyl side-chains. This agent has reduced toxicity compared with doxorubicin, and is effective in the treatment of solid tumours and leukaemias.

less common than incorporating it as a chain extender via methylmalonyl-CoA. We have already encountered this process in the formation of some branched-chain fatty acids with methyl substituents on the basic chain (see page 49). Of course, methyl groups can also be added to a fatty acid chain via SAM (see page 49), and there are also many examples for the methylation of poly-^-keto chains, several of which have already been discussed. Accordingly, methylation using SAM, and incorporation of propionate via methylmalonyl-CoA, provide two different ways of synthesizing a methylated polyketide (Figure 3.58). The former process is the more common in fungi, whilst Actinomycetes (e.g. Streptomyces) tend to employ propionate by the latter route. The incorporation of propionate by methylmalonate extender units can frequently be interrupted and normal malonate extenders are added, thus giving an irregular sequence of methyl side-chains.

The macrolide antibiotics* provide us with excellent examples of natural products conforming to the acetate pathway, but composed principally of propionate units, or mixtures of propi-onate and acetate units. The macrolides are a large family of compounds, many with antibiotic activity, characterized by a macrocyclic lac-tone ring, typically 12, 14, or 16 membered, reflecting the number of units utilized. Zear-alenone (Figure 3.59), a toxin produced by the

Methylation using SAM

SCoA

malonyl-CoA

Incorporation of propionate via methylmalonyl-CoA

propionyl-CoA

SCoA

0 ny

SCoA

CO2, ATP biotin co2h

SCoA

SEnz methylmalonyl-CoA

Figure 3.58

Fate of carbonyls:

SCoA

no reduction; cyclization to aromatic ring

OH O

OH O

O SEnz aldol reaction, II I

aromatization, ^^s/^o lactone formation zearalenone see Figure 3.60

O SEnz aldol reaction, II I

aromatization, ^^s/^o lactone formation

Figure 3.58

Fate of carbonyls:

no reduction; cyclization to aromatic ring

reduction y^r dehydration reduction

reduction reduction dehydration dehydration reduction reduction reduction y^r dehydration reduction reduction reduction dehydration dehydration reduction

enzyme-bound partially-reduced intermediate

Figure 3.59

zearalenone enzyme-bound partially-reduced intermediate

Figure 3.59

no reduction

O ii

I reduction T (ketoreductase)

I dehydration T (dehydratase)

I reduction f (enoylreductase)

fungus Gibberella zeae and several Fusarium species, has a relatively simple structure which is derived entirely from acetate - malonate units. It could be envisaged as a cyclization product from a poly-^-keto ester, requiring a variety of reduction processes and formation of an aromatic ring by aldol condensation near the carboxyl terminus (Figure 3.59). However, the poly-^-keto ester shown in Figure 3.59 would not be produced, since its reactivity might tend to favour formation of a polycyclic aromatic system (compare anthraquinones, page 63, and tetracyclines, page 89). Instead, appropriate reductions, dehydrations, etc, involving the P-carbonyl group are achieved during the chain extension process as in the fatty acid pathway (see page 36), and before further malonyl-CoA extender units are added (Figure 3.60). In contrast to fatty acid biosynthesis, where there is total reduction of each carbonyl group before further chain extension, macrolide biosynthesis frequently involves partial reduction, with the enzymic machinery being accurately controlled to leave the units at the right oxidation level before further chain extension

SEnz SEnz SEnz SEnz SEnz SEnz SEnz SEnz SEnz

O^ —¡- O=( O^ —^ O=( —O=( —O=( —O^ —O=( —O=( —

OH O

zearalenone

OH O

zearalenone

Figure 3.60

occurs. This then provides an enzyme-bound intermediate, which leads on to the final product (Figure 3.59). As a result, zearalenone is a remarkable example of an acetate-derived metabolite containing all types of oxidation level seen during the fatty acid extension cycle, i.e. carbonyl, secondary alcohol (eventually forming part of the lactone), alkene, and methylene, as well as having a portion which has cyclized to an aromatic ring because no reduction processes occurred in that fragment of the chain. There is now extensive genetic evidence from a variety of polyketide synthase systems to show that macrolide assembly is accomplished on a biological production line of multifunctional proteins organised as discrete modules, in which the developing polyketide chain attached to an acyl carrier protein is modified according to the appropriate enzyme activities encoded genetically, and is then passed on to another ACP prior to the next condensation and modification (see page 115 for more details).

Erythromycin A (Figure 3.61) from Saccha-ropolyspora erythraea is a valuable antibacterial drug and contains a 14-membered macrocycle composed entirely of propionate units, both as starter and extension units, the latter via methylmalonyl-CoA. In common with many antibacterial macrolides, sugar units, including amino sugars, are attached through glycoside linkages. These unusual 6-deoxy sugars are frequently restricted to this group of natural products. In erythromycin A, the sugars are L-cladinose and D-desosamine. Chain extension and appropriate reduction processes lead to an enzyme-bound polyketide in which one carbonyl group has suffered total reduction, four have been reduced to alcohols, whilst one carbonyl is not reduced, and remains throughout the sequence. These processes ultimately lead to release of the modified polyke-tide as the macrolide ester deoxyerythronolide, a demonstrated intermediate in the pathway to erythromycins (Figure 3.61; see also page 115). The stereochemistry in the chain is controlled by the condensation and reduction steps during chain extension, but a reassuring feature is that there appears to be a considerable degree of stereochemical uniformity throughout the known macrolide antibiotics. In the later stages of the biosynthesis of erythromycin, hydroxylations at carbons 6 and 12, and addition of sugar units, are achieved.

A combination of propionate and acetate units is used to produce the 14-membered macrocyclic ring of oleandomycin (Figure 3.62) from Strep-tomyces antibioticus, but otherwise many of the structural features and the stereochemistry of ole-andomycin resemble those of erythromycin A. One acetate provides the starter unit, whilst seven propi-onates, via methylmalonyl-CoA, supply the extension units (Figure 3.62). One methyl group derived

Fate of carbonyls: not reduced

SCoA

CO2H

SCoA

reduced dehydrated reduced

erythronolide

NMe2

erythronolide erythromycin A

D-desosamine

Fate of carbonyls: not reduced

SCoA

reduced dehydrated reduced reduced reduced deoxyerythronolide reduced reduced

L-cladinose deoxyerythronolide

Figure 3.61

CO2H

SCoA

SCoA

OH "V "OH SEnz

oleandolide

NMe2

D-desosamine

oleandomycin

L-oleandrose

Figure 3.62

from propionate has been modified to give an epoxide function. The sugar units in oleandomycin are L-oleandrose and D-desosamine. Spiramycin I (Figure 3.63) from Streptomyces ambofaciens has a 16-membered lactone ring, and is built up from a combination of six acetate units (one as starter), one propionate extender, together with a further variant, butyrate as chain extender. Butyrate will be incorporated via ethylmalonyl-CoA and yield an extension unit having an ethyl side-chain. This is outlined in Figure 3.63. In due course, this ethyl group is oxidized generating an aldehyde. Spiramycin I also contains a conjugated diene, the result of carbonyl reductions being followed by dehydration during chain assembly. Tylosin (Figure 3.64) from Streptomyces fradiae has many structural resemblances to the spiramycins, but can be analysed as a propionate starter with chain extension from two malonyl-CoA, four methylmalonyl-CoA, and one ethylmalonyl-CoA.

The avermectins* (Figure 3.67) have no antibacterial activity, but possess anthelmintic, insec-ticidal, and acaricidal properties, and these are exploited in human and veterinary medicine. The avermectins are also 16-membered macrolides, but their structures are made up from a much longer

co2h co2h

SCoA

CO2H

SCoA

SCoA

ethylmalonyl-CoA

Me2N

D-forosamine fx r

NMe2

^OR D-mycaminose

L-mycarose

R = H, leuconolide Ai

R = H, spiramycin I R = COCH3, spiramycin II R = COCH2CH3, spiramycin III

Figure 3.63

co2h

SCoA

co2h co2h

OH EnzS

O TT OH OH

I OMe OMe

D-mycinose

Figure 3.64

NMe2

u_JL

L-mycarose

Figure 3.64

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