Anticancer Antibiotics
Mode of Action:
Actinomycin D
Streptomyces and Micromonospora sps
Cartoon of intercalation and
minor groove binding of
actinomycins
SAR- 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
Streptomyces caespitosus
Reductive activation and bisalkylation
of DNA by Mitomycin C
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
Streptomyces plicatus and S. argillaceus
Medicinal Chemistry:
The sugars must be present in plicamycin for successful DNA binding and
magnesium ion also promotes the interaction.
Daunorubicin intercalation with DNA
S. peuceteus var. caesius
Streptomyces peucetius (and S. coeruleorubidus)
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