Anthracyclines & natural products((Lect-3-) .pdf

Medicinal Chemistry

1. Anti-Cancer Drugs
Antibiotics &
Natural Products
Medicinal Chemistry IV / 2
nd Semester / 4
th Class
Lecture 3
Dr.Narmin Hamaamin Hussen
2023-2024
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2. The Classification of Anticancer Drugs:
1.Alkylating agents
2. Antimetabolites
3.Antibiotics
4.Plant products
5.Hormones
6.Enzymes
7.Immuno therapy
8.Monoclonal antibodies
9.Radio-therapeutic agents
10.Cyto-protective agents
11.Miscellaneous
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3. 3. Antibiotics(mycin/bicin)
▪Many of the antineoplastic antibiotics are produced by the soil fungus Streptomyces. Both the antibiotic
and natural product classes have multiple inhibitory effects on cell growth; however, they primarily act to
disrupt DNA function and cell division.
▪ There are several mechanisms by which these agents target DNA, including intercalation, alkylation, and
strand breakage either directly or as a result of enzyme inhibition
Classification of Antibiotics(Cell cycle specific drugs) :
A.Anthracyclines
B.Actinomycin-D
C.Bleomycin
D.Mitomycin C
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4. ▪Initially discovered in the early 1960s when they were isolated from Streptomyces peucetius, hundreds of
compounds belonging to this class have subsequently been discovered of which five are used clinically in the
United States (doxorubicin, daunorubicin, idarubicin, epirubicin, and valrubicin).
▪DOX and DNR are natural compounds , EPI (4'-epidoxorubicin) and IDA (4-demethoxy daunorubicin) are synthetic
analogues (second generation anthracyclines) of DOX and DNR, respectively, from which the former two drugs
differ by relatively small chemical modifications
▪The conjugated systems found in these molecules impart a red color, which is reflected in the name.
▪Doxorubicin is probably the most important anticancer drug available because of its relatively broad spectrum of
activity
Anthracyclines
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5. First generation anthracyclines
Second generation anthracyclines
Third generation anthracyclines
Disaccharide Anthracyclines Morpholinyl-Anthracycline Derivatives
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6. ➢Doxorubicin
▪Doxorubicin is available as both the conventional dosage form and a liposomal preparation, both of which are
administered by infusion. Doxorubicin HCl powder is available in 10-, 20-, 50-, and 150-mg vials.
▪Doxorubicin is widely prescribed for the treatment of solid tumours (e.g., breast, ovary and gastrointestinal)
and haematologic malignancies (e.g., lymphoma and leukemia) in both adults and children.
▪The agent is rapidly taken up into tissues following injection with a distributive half-life of 5 minutes followed
by a slow elimination half-life of 20 to 48 hrs. The primary route of elimination is in the bile and feces.
Metabolism involves reduction of the C-13 ketone to yield doxorubicinol (active) along with cleavage of the
amino sugar to give the aglycone. The aglycones are also capable of undergoing redox cycling and producing
ROS.
▪ While an effective anti-tumor agent, doxorubicin causes cumulative and dose-dependent cardiotoxicity,
ranging from occult changes in myocardial structure and function to severe cardiomyopathy and congestive
heart failure that may result in cardiac transplantation or death
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7. Mechanism of action :
▪Bind to DNA and inhibit both DNA and RNA synthesis.
▪Produces breaks in DNA strands by activating topoisomerase II
and produces semiquinone free radicals. Semiquinone radicals
reduce molecular oxygen to superoxide ions and H2O2 that
mediates single strand scission of DNA.
▪ The anthracyclines are considered specific for the S phase of
the cell cycle.
▪In the case of doxorubicin and daunorubicin, specificity is
provided by the hydrogen bonding between O-9 of the
anthracycline and N-2 and N-3 of guanine.
▪The formation of covalent bonds between anthracyclines and
DNA also is supported by several studies in which formaldehyde
is produced by oxidation of cellular components or other
anthracycline molecules. This oxidation results from the
production of ROS such as H2O2, which are generated during
redox cycling of anthracyclines .
▪ The generated formaldehyde may then form a methylene bridge
between the 4-amino group of the anthracycline and the 2-
amino group of guanine in DNA
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8. Formation of anthracycline-DNA adduct.
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9. Mechanism of anthracycline-Induced Cardiotoxicity
▪The molecular mechanisms responsible for anthracycline-induced cardiotoxicity focusing on the pathogenic:
1.Role of Reactive Oxygen Species (ROS)
2. Anthracycline secondary alcohol metabolites
▪Although the anthracyclines produce several adverse effects that are typical for antineoplastics,
cardiotoxicity is a special concern with this class of agents. The associated cardiomyopathies and congestive
heart failure (CHF) have been related to the ability of these compounds to undergo redox cycling.
▪This is most notable in the case of daunorubicin and doxorubicin and less of a problem in the newer
derivatives, idarubicin and epirubicin.
▪However, several risk factors depending on patient and treatment characteristics may increase the incidence and severity
of anthracycline-related cardiotoxicity. Age at treatment (less than 18 or more than 65 years), sex (female), race (black),
genetic polymorphisms, pre-existing cardiovascular pathologies (coronary artery disease, left ventricular dysfunction,
hypertension etc.), metabolic (diabetes) or genetic (trisomy 21) diseases as well as higher administration rate,
concomitant radiation therapy and combination chemotherapy are known to increase the risk of developing
anthracycline-induced cardiotoxicity at much lower cumulative doses
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10. Process of anthracycline redox cycling
1.Role of Reactive Oxygen Species in Anthracycline Induced Cardiotoxicity
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11. 2- Role of Secondary Alcohol Metabolites in Anthracycline-Induced Cardiotoxicity
Metabolism of doxorubicin
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12. ➢Mitoxantrone Hcl (Dhad, Novantrone):
▪ Mitoxantrone is a synthetic agent, it is included with the natural products because
it is mechanistically similar to the anthracyclines. Produced in the late 1970s, it is a
derivative of a synthetic dye and is classified as an anthracenedione.
▪Mitoxantrone is supplied as a blue aqueous solution in 10- and 20-mg vials for IV
administration in the treatment of acute lymphoid leukemia, acute myeloid
leukemia, breast cancer, prostate cancer, non-Hodgkin’s lymphoma, and multiple
sclerosis.
▪In this case, however, other enzymes such as myeloperoxidase are responsible for
the generation of formaldehyde. Topoisomerase II is inhibited, and strand breakage
occurs similar to that seen with the anthracyclines.
▪ In contrast to the anthracyclines, mitoxantrone is not a substrate for the reductase
enzymes responsible for the conversion to the semiquinone so that ROS are not
generated by this process.
▪This has the effect of reducing the cardiotoxicity but not completely eliminating it,
and caution should be used especially in those patients with existing
cardiovascular problems.
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13. Antidot for cardiotoxicity of anthracycline (Iron chelators)
➢Dexrazoxane((Zinecard, Cardioxane)
▪Dexrazoxane has been used to protect the heart against the cardiotoxic side effects of chemotherapeutic drugs such as
anthracyclines, such as daunorubicin or doxorubicin or other chemotherapeutic agents.
▪ However, in July 2011 the European Medicines Agency (EMA) released a statement restricting use only in adult patients with
cancer who have received > 300 mg/m2 doxorubicin or > 540 mg/m2 epirubicin and general approval for use for
cardioprotection. It was speculated that dexrazoxane could be used for further investigation to synthesize new antimalarial
drugs
Mechanism:
▪As a derivative of EDTA, dexrazoxane chelates iron and thus reduces the number of metal ions complexed with anthracycline
and, consequently, decrease the formation of superoxide radicals.
▪Dexrazoxane binds iron before it enters cardiomyocytes which prevents the formation of the iron-anthracycline complex,
thereby preventing free radical formation and thus, cardiac damage. In addition, dexrazoxane can change the configuration
of topoisomerase 2β, preventing anthracyclines from binding to it, further preventing cardiomyocyte death, mitochondrial
dysfunction, and the suppression of anti-oxidant gene expression.
▪Dexrazoxane is a topoisomerase II inhibitor that, unlike anthracyclines, does not cause strand breaks. This additional
property is critical for its use as an antidote for anthracycline extravasation.
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14. Actinomycin-D
▪Dactinomycin is available in vials containing 0.5 mg of drug for reconstitution in sterile water for IV
administration This antibiotic is most effective in the treatment of rhabdomyosarcoma(skletal muscle) and
Wilms tumor(kidney) in children as well as in the treatment of choriocarcinoma(uterus), Ewing
sarcoma(bone), Kaposi sarcoma, and testicular carcinoma.
▪The actinomycins are a group of compounds that are isolated from various species of Streptomyces, all of
which contain the same phenoxazone chromophore but differ in the attached peptide portion
▪From this group emerged actinomycin D, which is known as
dactinomycin and contains identical pentapeptides bound through
an amide linkage utilizing the amino group of L -threonine with
carbonyls at positions 1 and 9 . 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
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15. Mechanism of action:
Representation of the dactinomycin–DNA complex.
DNA intercalation by actinomycin D.
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16. 4- Plant Products:
➢Vinca alkaloids
➢Taxanes
➢Epipodophyllotoxins
Vinca alkaloids
▪The vinca alkaloids are extracted from the leaves of Catharanthus roseus (periwinkle), and were originally
investigated for their hypoglycemic properties but latter found to possess antineoplastic actions.
▪The alkaloids are composed of a catharanthine moiety containing the indole subunit and the vindoline moiety
containing the dihydroindole subunit joined by a carbon–carbon bond
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17. ➢Vincristine and vinblastine differ only in the group
attached to the dihydroindole nitrogen, which is a methyl
group in vinblastine and a formyl group in vincristine.
➢Vincristine sulfate is available as a 1-mg/mL solution in 1-,2-,
and 5-mL vials for IV administration in acute leukemia.
➢Vinblastine is used in combination with other chemotherapy
drugs to treat Hodgkin's lymphoma (Hodgkin's disease) and
non-Hodgkin's lymphoma , and cancer of the testicles.
▪Vinorelbine is a semisynthetic material resulting from loss
of water across the 3,4 bond. It is FDA approved for the
treatment of NSCLC. The agent has also been used in treating
metastatic breast cancer, cervical cancer, uterine cancer, and
lung cancer especially in older patients or those with physical
difficulties
▪Vinorelbine is the most lipophilic of the vinca alkaloids
because of modifications of the catharanthine ring system
and dehydration of the piperidine ring. This allows the agent
to be quickly taken up into cells including lung tissue where
concentrations are 300-fold higher than plasma
concentrations. This is 3 to 13 times higher than the lung
concentrations seen with vincristine.
Structures of vinca alkaloids.
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18. Mechanism of action:
▪They are cell-cycle specific and phase specific, because they block mitosis in metaphase (M phase).
▪They block the ability of tubulin to polymerize to form microtubules.
▪The resulting dysfunctional spindle apparatus, frozen in metaphase, preventing chromosomal segregation and
cell proliferation.
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19. Taxanes
▪The taxanes, specifically, Taxol (or paclitaxel) was
discovered in the 1960s as part of a large-scale
screening program conducted by the National
Cancer Institute on plant extracts.
▪Taxol, isolated from the bark of the pacific yew
tree, proved to be active against various cancer
models, it’s used in the treatment of lung,
breast, and ovarian cancer.
▪The taxanes bind to tubulin at a site distinct
from the vinca alkaloids. Bind to stabilized
microtubules once they have formed, resulting
in the arrest of normal mitotic cell division and
subsequently cell death.
➢ Paclitaxel
➢ Docetaxel
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20. Structure-activity relationships of Taxol
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21. ▪The major toxicity seen with paclitaxel is dose-limiting myelosuppression that normally presents as
neutropenia. The previously mentioned hypersensitivity reactions occur but are greatly reduced by
antihistamine pretreatment.
▪The adverse effects profile for docetaxel is similar to that of paclitaxel but also includes reversible fluid
retention that is dose-related. Restriction of sodium intake and pretreatment with corticosteroids is usually
successful in minimizing this adverse effect. Peripheral neuropathy is seen with docetaxel but occurs less
often than with paclitaxel
Structures of the taxanes
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22. Epipodophyllotoxins
▪The epipodophyllotoxins are semisynthetic derivatives of podophyllotoxin, which is
isolated from the mayapple (mandrake) root and functions as an inhibitor of
microtubule function.
▪ Etoposide and its analog, teniposide are semisynthetic derivatives of the plant
alkaloid. The agent is approved for use in testicular cancer and small cell lung cancer
▪ They block cells in the late S to the G2 phase of the cell cycle.
▪ Their major target is topoisomerase II. Binding of the drugs to the enzyme-DNA complex(The etoposide
topoisomerase II complex then binds DNA, and strand cleavage occurs ) results in persistence of the transient,
cleavable form of the complex and, thus, renders it susceptible to irreversible double strand breaks.
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23. Structures of the epipodophyllotoxins.
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24. SARs of Epipodophyllotoxins

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25. Metabolism of epipodophyllotoxins
Metabolism of epipodophyllotoxins
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26. 6- Enzymes
▪New Cancer Treatment Uses Enzymes to Boost Immune
System and Fight Back.
▪Several enzymes are currently used as cancer biomarkers.
The use of protease urokinase plasminogen (uPA), as a
prognostic marker in human malignancies was first
reported in 1996 ,and its prognostic role has been studied
in colorectal, bladder, lung, gastric, cervical, and ovarian
cancers. Similarly, cathepsin D (another protease) has
proven to be a prognostic element in breast cancer .
▪Hexokinase activity has been shown to be associated with
the development of most cancers, and an array of reports
point to the importance of metabolic pathways in cancer
development .
▪Many enzymes have been reported to be under- or over-
expressed in various cancers
How is enzyme inhibition used in chemotherapy?
▪A substance that blocks the action of an enzyme. Enzymes help speed up chemical reactions in the body and
take part in many cell functions, including cell signaling, growth, and division. In cancer treatment, enzyme
inhibitors may be used to block certain enzymes that cancer cells need to grow
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27. Many enzymes have been reported to be under- or over-expressed in various cancers
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28. ➢ Aldehyde dehydrogenase 1 (ALDH1)
▪ALDH1 is responsible for oxidizing intracellular aldehydes, and
converts retinol to retinoic acid in cytosol during stem cell
differentiation . Reports suggest, ALDH1A1-positive tumor cells
demonstrate chemo-resistance in ovarian cancer.
▪Detoxification of aldehydes is critical for cellular health, as
aldehyde toxicity can lead to DNA damage, impaired cellular
homeostasis, and cell death .Another vital role of ALDH is in
retinoic acid metabolism, which is crucial for gene expression
and morphogenesis during embryonic development growth,
cellular differentiation, and homeostasis of vertebrates.
▪Elevated ALDH1 activity has been observed in breast cancer,
brain cancer, acute myeloid leukemia, and multiple myeloma
which suggests ALDH1 might be used as a marker of normal
and malignant cell populations . Studies on some lung cancer
cells have also reported ALDH1 up-regulation. Thus detection of
ALDH1 protein expression could be usable as a prognostic
biomarker for cancer.
➢4-Hydroxynonenal
▪4-HNE has 3 reactive groups: an aldehyde, a double-bond at carbon 2, and a hydroxy group at carbon 4.
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29. ➢Alkaline phosphatases (ALPs)
▪ALPs catalyze the hydrolysis of phosphate monoesters under alkaline conditions. These membrane-bound glycoproteins
are divided into four isozymes, that is, germ cell (GCALP), tissue nonspecific, intestinal, and placental ALPs (PALP).
▪The roles played by ALPs in a number of cellular processes have been elucidated and include cell growth, regulation of
phosphorylation, and cellular migration during embryonic development and apoptosis. Anomalies in the expressions of
ALPs have been associated with various human cancers.
▪ALPs have been reported to be highly expressed in choriocarcinoma and breast cancer-derived cells. PALP is a marker for
lung, gastrointestinal tract, ovarian, and testicular cancer. Plasma tissue nonspecific ALP or Tissue-nonspecific alkaline
phosphatase (TNALP) levels can indicate the presence of osteoblastic bone metastasis, osteosarcoma, and Paget’s disea
▪Higher ALP activities have also been reported in breast cancer patients , and Usoro et al. reported elevated Intestinal
alkaline phosphatase (IALP) levels in hepatocellular carcinoma
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30. Miscellaneous compounds
➢Asparaginase (l-asparaginase, elspar, L-asnase, cristanaspase)
▪Asparaginase is available in 10-mL vials for intramuscular and IV use in the treatment of acute lymphocytic
leukemia.
▪Tumor cells are unable to synthesize asparagine, and therefore must utilize what is available in the
extracellular environment. The agent acts by hydrolyzing extracellular asparagine to aspartate and ammonia.
The tumor cells are then deprived of a necessary nutrient, and protein synthesis is inhibited leading to cell
death. The agent is specific for the G1 phase of the cell cycle.
▪ Resistance occurs because of the development of the tumor cells ability to produce asparagine synthetase
that allows them to synthesize the required amino acid.
▪ Myelosuppression is not generally seen. An increased risk of bleeding and clotting is seen in half of the
patients taking the agent.
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31. ➢Hydroxyurea (Droxia, Hydrea):
▪The drug is available in a 500-mg capsule for oral use.
Hydroxyurea is often considered an antimetabolite drug,
and it is used alone or with other medications or radiation
therapy to treat a certain type of chronic myelogenous
leukemia (CML; a type of cancer of the white blood cells)
ovarian cancer, and essential thrombocytosis.
▪ The mechanism of action of hydroxyurea involves
inhibition of DNA biosynthesis by inhibition of the enzyme
ribonucleotide reductase. Ribonucleotide reductase (RNR)
is a key enzyme that mediates the synthesis of
deoxyribonucleotides, the DNA precursors, for DNA
synthesis.
▪The oral bioavailability is quite high approaching 100% and
the drug is distributed to all tissues. Hydroxyurea readily
enters the CNS and distributes to human breast milk. A
major portion of the total dose is excreted unchanged in
the urine.
▪ The drug has been shown to increase the toxicity of 5-FU,
and hydroxyurea may increase the effectiveness of some
antimetabolite HIV drugs.
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32. Miscellaneous antineoplastic agents
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33. Summary
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34. Summary
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