Anthracyclines

3.2 Anthracyclines

The anthracyclines i.e., the anthracycline antibiotics essentially contain an anthraquinone moiety fused with a non-aromatic ring:

There are quite a few ‘anthracycline antibiotics’ which have been isolated, characterized and evaluated for their therapeutic activities, namely: doxorubicin, epirubicin, aclacinomycin A, and idarubicin. However, mitoxantrone (mitozantrone), a synthetic structural analogue of the anthracyclinones wherein both the non-aromatic ring and the respective aminosugar have been duly replaced by aminoalkyl side-chains.

All the above mentioned potent compounds shall be described in the sections that follows:

3.2.1 Doxorubicin

Synonyms 14-Hydroxydaunomycin; NSC-123127; FI-106.

Biological Sources Doxorubicin, an anthracycline antibiotic is obtained from the cultures of Streptomyces peucetius var caesius.

Chemical Structure

(8S-cis)-10 [(3-Amino-2, 3, 6-trideoxy-α-L-lyxo-hexopyranosyl) oxy]-7, 8, 9, 10-tetrahydro-6, 8, 11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5, 12-naphthacenedione; [C₂₇H₂₉NO₁₁]

Characteristic Feature Doxorubicin has mp 229-231°C.

Uses

1. It has one of the broadest spectra of antitumour activity displayed by antitumour drugs.

2. It is extensively employed to treat acute leukemias, lymphomas, and a large number of solid tumours.

3. It has been found to inhibit the synthesis of RNA copies of DNA by virtue of the intercalation of the planar molecule between base pairs on the DNA helix.

Note: The inherent ‘sugar moiety’ affords an additional strength besides playing a critical role in the sequence-recognition required for the binding.

4. Doxorubicin also exerts a few of its cytotoxic effects on account of the inhibition of the enzyme topoisomerase II, which is solely responsible for both cleaving and resealing of the doublestranded DNA during the replic-tion process.

Doxorubicin Hydrochloride [C₂₇H₂₉NO₁₁.HCl] [Synonyms Adriacin; Adriblastina; Adriamycin]

1. It is obtained as orange-red coloured thin needles having mp 204-205°C (decomposes).

2. It has specific optical rotation [α]_D²⁰ + 248° (C = 0.1 in methanol).

3. It exhibits uvmax (methanol): 233, 252, 288, 479, 496, 529 nm.

4. It is found to be soluble in water, methanol, aqueous alcohols; and almost insoluble in acetone, benzene, chloroform, ethyl ether and petroleum ether.

5. The aqueous solutions show different colours at different pH ranges, e.g., at acidic pH yelloworange; at neutral pH orange-red; and at pH > 9 violet-blue.

6. The aqueous solutions are unstable at higher temperatures or at either alkaline or acidic pHs.

Note: Doxorubicin may reasonably be anticipated to be a carcinogen*.

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* Seventh Annual Report on Carcinogen (PB 95-10978, 1994), p. 86.

3.2.2 Epirubicin

Synonyms 4′-Epidoxorubicin; 4′-Epiadriamycin; Pidorubicin; 4′-EpiDX; IMI-28.

Biological Source It has the same biological source as that doxorubicin. It is the structural analogue of the anthracycline antibiotic doxorubicin, wherein the only point of difference is in the position of the C-4 hydroxy group of the sugar moiety.

Chemical Structure

4′-Epidoxorubicin; C₂₇H₂₉NO₁₁

Characteristic Features Epirubicin Hydrochloride [C₂₇H₂₉NO₁₁.HCl] [Synonyms Farmorubicin; Pharmorubicin].

1. It is obtained as red-orange crystals having mp 185°C (decomposes).

2. It has specific optical rotation [α]_D²⁰ + 274° (C = 0.01 in methanol).

Caution: Its solution should be protected from sunlight.

Uses

1. It is broadly employed as an antineoplastic agent.

2. It is proved to be particularly effective in the treatment of breast cancer, producing much lower side effects than doxorubicin itself.

Biosynthesis of Doxorubicin and Epirubicin The various steps involved in the biosynthesis of doxorubicin and epirubicin are as follows:

1. The propionyl-CoA is used not only as a ‘starter moiety’ but also as a chain-extender via the methylmalonyl-CoA. The Actinomycetes (e.g., Streptomyces) has a tendency to use propionate via methylation using SAM followed by incorporation of propionate by methylmalonyl-CoA.

Note: It has been observed that the incorporation of propionate by the methyl malonate extender units may undergo unusual frequent interruption, which process may be combated by the addition of further malonate extenders. The said phenomenon usually gives rise to an irregular sequence of methyl side-chains.

2. The alkanonic acid in the presence of S-adenosylmethiorine (SAM) and through aldol condensation yields aklaviketone.

3. The resulting aklaviketone undergoes reduction of O=C- at C-7 with NADPH generating the aklavinone.

4. Further aklavinone with NADPH in the presence of oxygen causes hydroxylation at C-11 to produce ε-rhodomycinone.

5. At this juncture thiamine diphosphate-D-glucose (TDP) yielding thiamine diphosphate-L-daunosamine is introduced. Consequently, a series of five sequential reactions, such as:

(i) glycosylation of 7-hydroxyl moiety; (ii) hydrolysis of ester; (iii) de-carboxylation 10-carboxylic acid group; (iv) oxidation to corresponding 13-ketone; and (v) methylation of 4-hydroxyl moiety, ultimately produces daunorubicin (daunomycin).

6. The resulting daunorubicin undergoes hydroxylation at C-14 in the presence of oxygenated NADPH finally yields doxorubicin (adriamycin).

7. Doxorubicin undergoes epimerization at C-4′ (see inset) in the following biosynthetic pathway,to produce epirubicin.

3.2.3 Aclacinomycin A

Synonyms Aclarubicin; Antibiotic MA 144 A1; NSC-208734; Jaclacin.

Biological Source It is obtained from Streptomyces galilacus.

Chemical Structure It is a complex glycoside of aklavinone (C₄₂H₅₃NO₁₅).

Characteristic Features

1. It is obtained as a yellow microcrystalline powder from a mixture of chloroform and hexane having mp 151-153°C (decomposes).

2. It has specific optical rotation [α]_D²⁴-11.5° (C = 1 in methylene chloride).

3. It has uv_max (methanol): 229.5; 259; 289.5; 431 nm (E^1%_1cm 550, 326, 135, 161); (0.1 N HCl) 229.5, 258.5, 290, 431 nm (E1%1cm 571, 338, 130, 161); (0.1 N NaOH) 239, 287, 523 nm (E^1%_1cm 450, 113, 127).

4. It is found to be soluble in chloroform, ethyl acetate; insoluble in ether, n-hexane, petroleum ether.

Identification Tests

1. To an aqueous solution of aclacinomycin A add a few-drops of NaOH solution when an intense reddish purple colour is obtained.

2. To a few mg of it add 0.5 ml of pure concentrated HCl when it gives a distinct yellow colouration.

Uses It shows an enhanced antineoplastic activity with much less cardiotoxicity.

3.2.4 Idarubicin

Synonyms 4-Demethoxy daunomycin; 4-Demethoxydaunorubicin; DMDR; IMI-30; NSC-256439.

Biological Source It is an orally active semi-synthetic structural analogue of daunorubicin (Section 3.2.2).

Chemical Structure

Characteristic Features Idarubicin Hydrochloride: [C₂₆H₂₇NO₉.HCl] [Synonyms: Idamycin, Zavedos]: It is obtained as orange crystalline powder having mp 183-185°C. It has specific optical rotation [α]_D²⁰ + 205° (C = 0.1 in methanol).

Uses

1. It is mostly used as an antineoplastic agent.

2. It may show increased activity with comparatively much lesser cardiotoxicity.

Note: The major drawback of structurally related and modified semi-synthetic doxorubicintype antibiotic is due to their significant cardiotoxicity that invariably comes into being by virtue of the distinct inhibition of cardiac Na⁺, K⁺-ATpase.

3.2.5 Mitoxantrone

Synonyms Mitozantrone; DHAQ; NSC-279836.

Chemical Structure Mitoxantrone is purely a ‘synthetic structural analogue’ of the ‘anthracyclinones’ wherein two important components viz., the aminosugar and the non-aromatic ring have been strategically replaced with a pair of amino-alkyl side chains i.e., amino-ethyl.

1, 4-Dihydroxy-5, 8-bis [[2-[(2-hydroxyethyl) amino] ethyl] amino]-9, 10-anthracenedione; (C₂₂H₂₈N₄O₆).

Characteristic Features

1. It is obtained as crystals from a mixture of ethanol and hexane having mp 160-162°C.

2. It has uvmax (ethanol): 244, 279, 525, 620, 660 nm (log ε 4.64, 4.31, 3.70, 4.37, 4.38).

3. It is sparingly soluble in water; slightly soluble in methanol; and almost insoluble in acetone, acetonitrile, chloroform.

Mitoxantrone Dihydrochloride [C₂₂H₂₈N₄O₆.2HCl] [Synonyms: Novantrone; DHAD; CL-232315; NSC-301739].

1. It is obtained as a hygroscopic blue-black solid from a mixture of water and ethanol having m_p 203-205°C.

2. It has uv_max (water): 241, 273, 608, 658 nm (ε 41000, 12000, 19200, 20900).

3. It is found to be sparingly soluble in water; slightly soluble in methanol; and practically insoluble in acetone, acetonitrile, chloroform.

Uses

1. Mitoxantrone has a marked and pronounced reduced toxicity as compared to doxorubicin (Section 9.3.2.1)

2. It is found to be extremely effective and useful in the treatment of leukemias and solid tumours exclusively.

Source:Pharmacognosy And Pharmacobiotechnology By Ashutosh Kar