2.Antitumor Antibiotics

SAR of antitumour antibiotics, Medicinal chenistry

1. 1 A. Cytotoxic drugs 1. Alkylating agents 2. Platinum coordination complexes 3.Antimetabolites 4 . Antibiotics 5 . Plants B. Targeted drugs Tyrosine protein kinase inhibitors EGF receptor inhibitors Angiogenesis inhibitors Biological response modifiers C. Hormonal drugs CLASSIFICATION OF ANTICANCER DRUGS

2. Drugs from Natural source A variety of the anticancer agents available today are derived from natural sources Microbial sources (antibiotics) and Plants Both the antibiotic and natural product from plants classes have multiple inhibitory effects on cell growth; however, They primarily act to disrupt DNA function and cell division.

3. Mechanisms by which these agents target DNA is Intercalation, Alkylation, and Strand breakage either directly or as a result of enzyme inhibition. Steps in Intercalation Intercalating drugs contain a planar aromatic or heteroaromatic ring system which can slip into the double helix of DNA and distort its structure. Drug should induce a cavity between base pairs so that insertion may occur b/n drug and DNA. The interaction of the intercalator (drug) and the adjacent base pairs of DNA occurs by the overlap of p-orbitals of the intercalator and the base pairs. The p-orbitals of the intercalator/ intercalation species are provided by a combination of aromatic and conjugated systems that impart the planarity required for intercalation.

4. The side chains of intercalator has a cationic moiety , which may form ionic bonds with the anionic phosphate backbone in DNA. The overall result of these interactions is to cause a local bend or kink or cut in DNA resulting in a local shape distortion . Inhibition of topoisomerase /DNA gyrase (Topoisomerase enzymes are responsible for the unwinding and relaxation of DNA so that transcription may occur)

5. Classification of Antitumor Antibiotics drugs Many of the antineoplastic antibiotics are produced by the soil fungus Streptomyces . Anthracyclines :  Doxorubicin, Daunorubicin , Epirubicin , Mitoxantrone , and Idarubicin . Actinomycins / Chromomycins :   Dactinomycin and Plicamycin . Miscellaneous:   Mitomycin and Bleomycin .

6. Antracyclines Doxorubicin (previously called adriamycin ) belongs to a group of naturally occurring antibiotics called the anthracyclines , and was isolated from Streptomyces peucetius in 1967. It is very similar in structure to Daunorubicin —differing only in one hydroxyl group at C9 acetyl group in daunorubicin & hydroxy acetyl group in doxorubicin .

7. The second generation anthracyclines E pirubicin and Idarubicin lacks the methoxy group at C4 , so it is more polar and has an altered metabolism which prolongs its half-life.

8. SAR The anthraquinone chromophore is an important structural feature of the anthracyclines . the anthraquinone chromophore , consisting quinone and a hydroquinone moiety on adjacent rings. The phenolic hydroxy groups present in this core were found to undergo ready acylation and alkylation under standard reaction conditions. It has been shown that, O- methylation of the C-6 or C-11 phenolic groups results in analogs with markedly reduced activity, whereas C-4 modifications such as demethylation and deoxygenation do not affect bioactivity. The transformation of the C-5 carbonyl to the corresponding imino functionality resulted in an analog that retained activity and was found to be significantly less cardiotoxic than the parent compound. Ring-A, alicyclic moiety bearing the two-carbon side chain group and the tertiary hydroxyl group at C-9 and also having a chiral hydroxy group at C-7, which in turn connected to the aminosugar unit; the amino sugar residue, attached to the C-7 hydroxy group through an a-glycosidic linkage;

9. Iron-mediated generation of free oxygen radicals that damage the DNA, proteins and cell membranes

10. Drug-DNA Complex

11. Mitoxantrone It is a simplified, synthetic analogue of the anthracyclines where the tetracyclic ring system has been ‘ pruned ’ back to the planar tricyclic system required for intercalation. There is no sugar ring which is responsible for cardio toxic side effects. The pharmacophore groups are highlighted in box and which are responsible For binding with DNA base Pairs. Anthrace ring interculate b/n DNA base pairs.

12. Uses of Anthracyclines Doxorubicin is used to treat a broad spectrum of solid tumours, as well as acute leukaemias , lymphomas, and childhood tumours. Daunorubicin is indicated for acute leukaemias . Epirubicin is considered effective against breast cancer. Idarubicin is used in the treatment of haematological malignancies and can be given orally. Both epirubicin and idarubicin are second-generation anthracyclines with less cardiac toxicity than doxorubicin or daunorubicin . Mitoxantrone is used for the treatment of certain leukaemias and lymphomas, and for advanced breast cancer.

13. Side effects of Anthracyclines Causes cardiotoxicity Interference with ryanodine receptors of the sarcoplasmic reticulum in the heart muscle cells Sugar residue is one of the cause for cvs toxicity Free-radical formation in the heart Leads to forms of congestive heart failure, often years after treatment Counteract with dexrazoxane Liposomes can be useful as carriers to deliver doxorubicin to target tumours and this approach is associated with less cardiac toxicity. Extravasation injury produce extensive local necrosis.

14. Extravasation Injury by Doxorubicin Redness , swelling blisters Tissue necrosis surgery to remove tissue permanent damage

15. Actinomycins The Actinomycins are a group of compounds that are isolated from various species of Streptomyces , Phenoxazone chromophore And has di pentapeptide portion The 1 St drug from this group is Actinomycin D which is known as Dactinomycin Other Pilcamycin

16. Actinomycin -D/ Dactinomycin Phenoxazone chromophore And has di pentapeptide portion The pentapeptides namely L- threonine , D- valine , L-proline, sarcosine, and L-methylvaline form a lactone via the side chain hydroxyl of L- threonine and the carboxyl group of L- methylvaline An amide linkage is present b/n the amino group of L- threonine and carbonyls of 1 and 9 of Phenoxazone chromophore

17. The structural feature of dactinomycin important for its mechanism of cytotoxicity is the planar phenoxazone ring, which facilitates intercalation between DNA base pairs. The peptide loops are located within the minor groove and provide for additional interactions. Dactinomycin binds noncovalently to double-stranded DNA by partial intercalation between adjacent guanine cytosine bases resulting in inhibition of DNA function. Additional hydrophobic interactions and hydrogen bonds are formed between the peptide loops and the sugars and base pairs within the minor groove.

18. M echanism of action of Dactinomycin Minor Groove D D By an effect on topoisomerase II that unwinds the DNA helix for replication It intercalates, in the minor groove of DNA, between adjacent guanine-cytosine pairs thus preventing transcription. DNA synthesis may also be inhibited, and the agent is considered as cell cycle specific for the G1 and S phases. Block DNA Gyrase/ topoisomerase Uses is given mainly intravenously to treat paediatric solid tumours, including Wilm's tumour and Ewing's tumour

19. Mitomycin C It is a natural product isolated from Streptomyces verticillataus as well as from other sources.

20. Mitomycin Reductive activation and bisalkylation of DNA by Mitomycin C Streptomyces caespitosus

21. Interstrand and intrastrand alkylation of DNA by bioreductively activated mitomycin C.

22. Uses of Mitomycin C Adenocarcinoma of the stomach , colon , or pancreas. Its use and application in ophthalmology has been increasing in recent years because of its modulatory effects on wound healing. Current applications include Pterygium surgery, Glaucoma surgery, Corneal refractive surgery, Cicatricial eye disease, Conjunctival neoplasia and allergic eye disease.