Anticancer Antibiotics

Mode of Action:

Actinomycin DStreptomyces and Micromonospora sps

SAR- Actinomycins

Cartoon of intercalation and minor groove binding of

actinomycins

Medicinal Chemistry:

• Replacement of the normal side chains by simple amines leads to inactive products. Most of the other side-chain variations have led to compounds with reduced in-vivo potency. Some chemical alterations in the chromophoric phenoxazinone moiety have also been done. After several analogues were tested, it has been concluded that the C-2 and the C-7 positions can be substituted with retention of significant activity.

• Groups that can be introduced on C-2 and C-7:(2-OH, 2-Cl and 2-amino groups) C-2 C1 analog on catalytic reduction results in the protio analog, which is inactive. The C-2 chloro analog can be halogenated with chlorine or bromine to produce the C-2 chloro-C7 chloro or bromo analogs. These in turn can be solvolyzed to the C-2 amino-C7 halo analogs. Nitration and hydroxylation at the C-7 position can be accomplished. The C-7 ally1 ether when epoxidized to produce an analog can not only intercalate by virtue of its aromatic rings but can also alkylate DNA.

Streptomyces verticillus

Medicinal Chemistry: • The essential central core of bleomycin provides a chelating environment for

transition metals, especially Cu (I) and Fe (II). The branched glycopeptide side chain is less essential for activity and helps in facilitating passage across cell membranes and to assist in oxygen binding. Removal of the sugars and the oxygen to which they are attached produces molecules that are fully active but distinct from bleomycin itself. The dipeptide unit is a linker arm but contributes key hydrogen bonding and perhaps other binding interactions that intensify activity and produce degrees of base specificity to the cleavages. The bithiazole unit and its pendant terminal cation are important in DNA targeting of the drug. These contributions were uncovered by the chemical synthesis of analogs that could not readily have been prepared by degradation of bleomycin itself or by directed biosynthesis. Partial chemical synthesis, with or without the aid of enzymes, has also produced a variety of analogs through modifications of this peripheral side-chain array. The terminal bithiazole and its pendant amides are the portion of the molecule that binds to DNA. For the purpose of making analogs, the charged dirnethylsulfonium group is monodemethylated through the agency of heat. The resulting compound is then cleaved to bleomycinic acid by use of cyanogen bromide followed by mild alkaline treatment. Some soil microorganisms possess acylagmatine amidohydrolase capable of converting bleomycin to bleomycinic acid. Bleomycinic acid is then converted to the desired amides by use of water-soluble carbodimide chemistry.

•The phleomycins (11) are related in that one of the thiazole rings has been reduced to its C-44,45-dihydro analog. The phleomycins have substantial antitumor activity but are very nephrotoxic for clinical use. The cliomycins (12), tallysomycins (13), zorbamycins (14), zorbonamycins, platomycins, and victomycins are also structurally related to the bleomycins. None of these various alternative substances has displaced the bleomycin complex from the market, even though many possess significant antitumor properties. The specific potencies and toxicities vary widely with structural variations. In the presence of a mild base, metal-free bleomycin isomerizes to isobleomycin through an acyl migration of the carbamoyl moiety from position 22 to 23 of the mannosyl group. Copper (I) bleomycin, under the same conditions, slowly isomerizes at its masked aspartamine moiety attached to the pyrimidine substituent (at C-6). This isomer is substantially less active than bleomycin itself. Bleomycin chelates with various transition metals, the most relevant of which are iron (II) and copper (I), to form the corresponding complexes. The iron complex binds oxygen and becomes oxidized, producing the hydrogen radical and the hydroperoxyl radical. The bithiazole moiety intercalates into DNA and the complex is stabilized by electrostatic attractions between the sulfonium or ammonium side chains with the phosphate backbone of DNA. This fixes the drug at DNA, whereupon the reactive oxygen species generated by its transition-metal complex breaks the DNA molecule at the sugar back-bone, thus releasing purine and pyrimidine bases. Acceptable variations involve substitution of various groups onto bleomycinic acid and a variety of other comparatively trivial changes such as partial reduction of the thiazole moieties and alterations of the amino acids near the bleomycinic acid carboxyl group.

Generation of reactive oxygen species by transition metal chelates of bleomycins.

Mitomycin

Reductive activation and bisalkylation of DNA by Mitomycin C

Streptomyces caespitosus

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

Medicinal Chemistry:

• More than a thousand analogs have been prepared by semisynthesis but none of these agents has succeeded in replacing mitomycin C. The mitomycin C analogs are less toxic than mitomycin A derivatives. Most modifications have been achieved at the N-H, C-7, C-6, and C-10 positions. It is noted that the C-6 and C-7 positions play only an indirect role in the activation of the ring system, so substitutions there might be regarded as primarily significant in altering the pharmacokinetic properties of the mitomycins. Thiols activate the methoxy analogs but not the amino analogs. Mechanistically, both series arrive at the same bisalkylating species in-vivo but through different routes. This may help rationalize why mitomycin A is both more potent and more cardiotoxic than mitomycin C. The results of a comparison of physicochemical properties and biological activity of the mitomycins led to the conclusion that potency correlates with uptake, as influenced primarily by log P, and also with the redox potential. The metabolism of mitomycin C in vivo primarily leads through reduction and loss of methanol to a dihydromitosene end product. Interception by DNA, on the other hand, leads to alkylation of the latter instead.

Plicamycin

Medicinal Chemistry:The sugars must be present in plicamycin for successful DNA binding and magnesium ion also promotes the interaction.

Streptomyces plicatus and S. argillaceus

Daunorubicin intercalation with DNA

Streptomyces peucetius (and S. coeruleorubidus)

S. peuceteus var. caesius

Medicinal Chemistry:

• The structure-activity relationship (SAR) of the anthracycline structural core can be divided into three major components: (1) Ring-D, 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; (2) the amino sugar residue, attached to the C-7 hydroxy group through an a-glycosidic linkage; the anthraquinone chromophore, consisting quinone and a hydroquinone moiety on adjacent rings. The C-13 and C-14 positions of anthracyclines are sites for functional derivatization. Thus, the 13-keto functionality has been subjected to reduction, deoxygenation, hydrazide formation, without adversely affecting the bioactivity. Similarly, incorporation of various ester and ether functionalities at C-14, through the initial halide formation and subsequent displacement of halogen with nucleophiles, found to be a useful in modulating the activity of the parent anthracyclines. However, homologation of the C-9 alkyl chain or introduction of amine functionalities at C-14 is detrimental to activity. Also, the 9,10-anhydro or the 9-deoxy analogues results in decreased activity.

• The natural stereochemical configurations at C-7 and C-9 were found to be an important contributor to bioactivity, wherein it has been proposed that H-bonding between the two cis-oxygen functionalities at these positions stabilizes the preferred half-chair conformation of the D-ring. The amino sugar residue of the various anthracyclines is an essential requirement for bioactivity. Among the various SAR studies involving the carbohydrate core, it has been seen that attachment of this moiety to the anthracycline nucleus through an a-anomeric bond is necessary for optimum activity. Conversion of the C-3' amine group to the corresponding dimethylamino or morpholino functionalities confers improved activity; however, acylation of the amine (the exception being trifluoroacetyl) or its replacement with a hydroxy group results in loss of activity. Conversion of the C-4' hydroxy group to its corresponding methyl ether or C-4' epimerization or deoxygenation has a negligible effect on bioactivity. In more recent studies, novel disaccharide analogs of doxorubicin and idarubicin have been found to exhibit impressive antitumor activity.

• The anthraquinone chromophore is an important structural feature of the anthracyclines. 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.

Drug Uses

Dactinomycin Wilm's tumor, rhabdomyosarcoma, metastatic and nonmetastatic choriocarcinoma, nonseminomatous testicular carcinoma, Ewing's sarcoma, nonmetastatic Ewing's sarcoma, and sarcoma botryoides.

Bleomycin Squamous cell carcinomas, Hodgkin's disease, testicular and ovarian carcinoma, and malignant pleural effusion.

Mitomycin Adenocarcinoma of the stomach, colon, or pancreas.

Plicamycin Testicular tumors, hypercalcemia and hypercalciuria associated with advanced cancer, particularly involving paget’s bone disease.

Daunorubicin Acute myelogenous and lymphocytic leukemias.

Doxorubicin Acute lymphoblastic leukemia, acute myeloblastic leukemia, Wilms' tumor, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, Hodgkin's and non-Hodgkin's lymphomas, bronchogenic carcinoma, and gastric carcinoma.

Epirubicin Breast cancer

Drug Toxicity

Dactinomycin Renal, hepatic abnormalities, GI ulcerations, proctitis, anemia, blood dyscrasias and esophagitis.

Bleomycin Pulmonary fibrosis

Mitomycin Serious cumulative bone marrow suppression, thrombocytopenia and leukopenia that can contribute to the development of overwhelming infectious disease. Irreversible renal failure as a consequence of hemolytic uremic syndrome. Occasionally adult respiratory distress syndrome has also been seen.

Plicamycin Severe thrombocytopenia, hemorrhagic tendency, renal impairment, mutagenicity, and interfere with fertility, anorexia, stomatitits, depression phlebitis, facial flushing, hepatotoxicity, and electrolyte disturbances (decrease in serum calcium, potassium, and phosphate levels) are also encountered.

Daunorubicin CHF, secondary leukemia, renal failure, carcinogenesis, mutagenesis, teratogenicity, and fertility impairment.

Doxorubicin Hepatic damage