Anticancer Agents PDF

# Anticancer agents ## Cancer Known medically as a malignant neoplasm, is a broad group of diseases involving unregulated cell growth affecting different organs and systems of the body. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invading nearby parts of the body...

# Anticancer agents ## Cancer Known medically as a malignant neoplasm, is a broad group of diseases involving unregulated cell growth affecting different organs and systems of the body. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invading nearby parts of the body. The causes of cancer are diverse, complex, and only partially understood. Many things are known to increase the risk of cancer, including tobacco use, dietary factors, certain infections, exposure to radiation, lack of physical activity, obesity, inherited genetic defects and environmental pollutants. While cancer can affect people of all ages, and a few types of cancer are more common in children, the risk of developing cancer generally increases with age. In 2012, about 165,000 children under 15 years of age were diagnosed with cancer. The most common types of cancer in males are lung cancer, prostate cancer, colorectal cancer and stomach cancer. In females, the most common types are breast cancer, colorectal cancer, lung cancer and cervical cancer. * In 2015 about 90.5 million people had cancer. * In 2018 about 18.1 million new cases of cancer. * It caused about 9.6 million deaths. ## Rationale of Antineoplastic agents The rationale depends on that cancer cells multiply at a rate greater than all normal cells. ## Obstacles of cancer chemotherapy * Selectivity * Must kill ALL cancer cells * Minimal harm to normal cells ## Classes of anticancer agents 1. Alkylating agents 2. Antimetabolites agents 3. Antibiotics 4. Natural Products 5. Protein Kinase Inhibitors 6. Hormone-based Therapy ## Classification of Anticancer agents ### I) Alkylating agents An alkylating antineoplastic agents are used in cancer treatment that attaches an alkyl group to DNA. The alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring. Since cancer cells, in general, proliferate faster and with less error-correcting than healthy cells, cancer cells are more sensitive to DNA damage - such as being alkylated. Most of the alkylating agents are also carcinogenic. These drugs act as the same mechanism that makes them toxic allows them to be used as anti-cancer drugs. #### A) Classical Alkylating agents ##### i) Nitrogen mustard The nitrogen mustards are cytotoxic chemotherapy agents similar to mustard gas. Although their common use is medicinal, these compounds can also be used as chemical warfare agents. Nitrogen mustards are nonspecific DNA alkylating agents. ###### Mechanism of action They act via alkylation i.e transfer of their alkyl groups to various cellular constituent leading to cellular lethality. It forms DNA-DNA inter or intrastrand crosslinks between the DNA bases guanine and adenine and between guanine and guanine. DNA crosslinking prevents DNA replication. Because the intrastrand DNA crosslinks cannot be repaired by cellular machinery, the cell undergoes apoptosis. ###### 1- Mechlorethamine 2,2-dichloro-N-methyldiethyl-amine hydrochloride It is the prototype of nitrogen mustard alkylating agents. ###### Synthesis It has been derivatized into the estrogen analogue Estramustine, used to treat prostate cancer. ###### 2- Cyclophosphamide (Endoxan®) It is a Prodrug, it is converted by liver enzymes to active metabolite 4-hydroxy cyclophosphamide which occurs in equilibrium with the open chain aldophosphamide form. Then Non- enzymatic decomposition in the cancer cell to generate phosphoramide mustard which form the azeridinium ion. ###### Bio-activation ###### Synthesis ###### Selectivity The high level of Phosphoramidase enzyme present in some tumor cells leads to greater concentration of alkylating agent in these cells and results in some selectivity of action. ###### Toxicity The acrolein released is toxic to the kidneys and the bladder because it alkylates cysteine residues in cell proteins. This toxicity is reduced by co-adiminstration of sulfhydryl donors as N-acetylcysteine or Mercapto-ethyl sulphonate which interacts with acrolein. ###### 3- Ifosfamide It is an isomer of cyclophosphamide. Must be activated by hepatic enzymes. ###### 4- Trofosfamide It is considered as a Prodrug. It is rapidly dechloroethylated Isofosfamide (predominant) and cyclophosphamide, repectively. ###### 5- Melphalan (Alkeran®) (2S)-2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl} propionic acid It is a aromatic mustard able to stabilize the lone pair of electron on the mustard nitrogen. Less reactive than aliphatic mustard, thus it has greater opportunity for distribution to cancer cells and less incidence of severe side effects. ###### 6- Chlorambucil (Leukeran®) 4-[bis(2-chlorethyl)amino]benzenebutanoic acid It is a Prodrug metabolized by beta-oxidation to give phenylacetic acid mustard active metabolite. #### SAR * Bis-(2-chloroethyl) amino group is essential for activity. * Chlorine atom has maximum activity. * Increase the length of side chain than 2 C-atom gives no antineoplastic activity. * The structure of nitrogen mustards differs only in the nature of the group (R) attached to the amino nitrogen (It can either be aliphatic or aromatic). * (R) is the prime determinant of chemical reactivity, oral bioavailability and the nature and extent of side effects. * An aliphatic nitrogen substituent will push the electrons to the amine through sigma bonds. This electronic enrichment enhances the nucleophilic character of the lone pair of electrons and increases the speed of aziridinium ion formation. #### SAR * Conversely, an aromatic substituent (phenyl) conjugated with the mustard nitrogen will stabilize the lone pair of electrons through resonance. This slows down the rate of aziridinium ion formation and DNA alkylation. * Thus, aromatic mustards have a reactivity sufficiently controlled to permit oral administration and attenuate the severity of side effects. #### ii) Aziridine Derivatives They are compoumds that transformed into active Aziridinium ion. ###### 1- Triethylenemelamine (Tretamine®) 2,4,6-Tris(aziridin-1-yl)-1,3,5-triazine It is used for treatment of Lymphomas and chronic leukemia. ###### 2- Thiotepa (ThioTEPA) N,N'N'-triethylenethiophosphoramide 1,1',1"-Phosphorothioyltriaziridine It is used parenterally in the treatment of breast, overian, and bronchogenic carcinomas and malignant lymphomas. It is metabolized by oxidative desulfuration to give Triethylenphosphoramide (TEΡΑ). ###### Synthesis #### iii) Alkylsulphonate Derivatives ###### Mechanism of action This occurs through a reaction in which the relatively nucleophilic guanine N7 (Nu) attacks the carbon adjacent to the mesylate (methyl sulphonate) good leaving aroun ###### 1- Busulfan (Myleran®) butane-1,4-diyl dimethanesulfonate ###### Synthesis #### iv) Nitrosourea Derivatives Nitrosoureas are a class of compounds that include a nitroso (R-NO) group and a urea. ###### Mechanism of action These compounds undergo decomposition in aqueous solution producing. Alkyl diazohydroxide which is further decomposed to chroloethyl carbonium ion that alkylate guanine base in DNA. Isocyanate moiety that carbamoylate important functional groups in protein, as NH2 group. ###### 1- Carmustine / BCNU (BICNU®) 1,3-Bis(2-chloroethyl)-1-nitrosourea It is a mustard gas-related ẞ-chloro-nitrosourea compound. ###### Synthesis ###### 2- Lomustine / CCNU (CeeNU®) N-(2-chloroethyl)-N-cyclohexyl-N-nitrosourea ###### Synthesis Due to high lipophilicity, Both can Cross BBB and thus could be used in the treatment of several types of brain cancer. ###### 3- Streptozotocin (Zanosar®) Streptozotocin is a glucosamine-nitrosourea compound. It is particularly toxic to the insulin-producing beta cells of the pancreas in mammals. It is used in medicine for treating certain cancers of the Islets of Langerhans. It is also used in medical research to produce an animal model for Type 1 diabetes in large dose as well as Type 2 diabetes with multiple low doses. #### B) Non-classical Alkylating agents ##### i) Triazine Derivatives ###### 1- Dacarbazine 5-(3,3-Dimethyl-1-triazino)-1H-imidazole-4-carboxamide It is used in the treatment of various cancers, malignant melanoma, Hodgkin lymphoma, sarcoma, and islet cell carcinoma of the pancreas. Dacarbazine is bioactivated in liver by demethylation and then to diazomethane (H₂C=N=N) that give the methanediazonium (H3C-NΞΝ), which is the alkylating agent. ##### ii) Imidazotetrazine Derivatives ###### 1- Mitozolomide ###### 2- Temozolomide (Zanosar®) Temozolomide, which has been in clinical use since 1999, is a less toxic analogue of Mitozolomide. Temozolomide is an imidazotetrazine derivative of the alkylating agent Dacarbazine. It produce diazomethane (H₂C=N=N) that give the methanediazonium (H₂CNEN), which is the alkylating agents. ###### Mechanism of action ##### iii) Hydrazine Derivatives ###### 1- Procarbazine (Matulane®) N-isopropyl-4-[(2-methylhydrazino) methyl]benzamide Its mechanism of action is not fully understood, however, it is believed to act as alkylating agent by free radical reactions. It undergoes oxidation to azoprocarbazine in the presence of metalloproteins. Isomerization of this azocompound followed by hydrolysis gives methylhydrazine and p-formyl-N-isopropyl benzamide. Methylhydrazine is oxidized to methyldiazine which can be decomposed to methyl free radical that acts as the alkylating agent. ### C) Alkylating-like agents These agents do not have an alkyl group, but nevertheless damage DNA. They act in a similar manner that permanently coordinate to DNA to interfere with DNA repair, so they are sometimes described as "alkylating-like". These agents also bind at N7 of quanine. #### i) Platinum-based chemotherapeutic drugs Organoplatinum antineoplastic agents contain an electron-deficient metal atom that acts as a magnet for electron-rich DNA nucleophiles. Like nitrogen mustards, organoplatinum complexes are Bifunctional and can accept electrons from two DNA nucleophiles. Intrastrand cross-links most frequently occur between adjacent guanine residues referred to as diguanosine dinucleotides. ###### 1- Cisplatin It is the first member of platinum-containing anti-cancer drugs (prototype). Cisplatin is administered intravenously as short-term infusion in normal saline for treatment of solid malignancies. One of the chloride ligands is slowly displaced by water, in a process termed aquation. The aqua ligand in the resulting is itself easily displaced, allowing the platinum atom to bind to DNA, guanine bases. Subsequent to formation of, crosslinking can occur via displacement of the other chloride ligand, typically by another guanine. These crosslinks interfering with cell division. ###### 2- Carboplatin It is more stable and has reduced side-effects compared to its parent compound Cisplatin. ###### 3- Oxaliplatin Oxaliplatin is a third-generation cis-platinum derivative. Oxaliptatin is typically administered with Fluorouracil and Folinic acid in a combination known as [FOLFOX (FOLinic acid- - Flurouracil - Oxaliplatin)] for the treatment of colorectal cancer. ### II) Antimetabolite Anticancer agents An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with their biosynthesis as they might be metabolized instead of the normal substrate, and enter in a metabolic pathway so that at the end it is incorporated into a key molecule which can not function properly. The presence of antimetabolites can have toxic effects on cells, such as halting cell growth and cell division, so these compounds are used as chemotherapy for cancer. #### A) Purine analogues ###### 3,7-dihydropurine-6-thione ###### 6-Mercaptopurine ###### 2-amino-1H-purine-6(7H)-thione ###### Thioguanine Both are hypoxanthine analogue that compete with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyl transferase. In addition Fludarabine inhibits DNA synthesis by interfering with ribonucleotide reductase and DNA polymerase. #### B) Pyrimidine analogue ###### 1- Fluorouracil (Efudex®) 5-fluoro-1H,3H-pyrimidine-2,4-dione ###### Tegafur Tegafur is a fluorouracil prodrug. ###### Mechanism of action It is a suicide inhibitor and works through irreversible inhibition of thymidylate synthase. Interrupting the action of this enzyme blocks synthesis of the pyrimidine thymidine, which is a nucleoside required for DNA replication. ###### 2- Floxuridine (5-fluorodeoxyuridine) ###### 3- Gemcitabine (Gemzar®) Uses and mechanism of action similar to 5-Fluorouracil. ###### 4- Cytarabine Cytarabine also possesses antiviral activity Its mode of action is due to its rapid conversion into cytosine arabinoside triphosphate, that inhibits both DNA and RNA polymerases and nucleotide reductase enzymes needed for DNA synthesis. ### C) Dihyhdrofolate reductase inhibitors #### Antifolates They are mainly folic acid analogue, and owing to structural similarity with it, they bind and inhibit the enzyme dihydrofolate reductase (DHFR), and thus prevents the formation of tetrahydrofolate. Because tetrahydrofolate is essential for purine and pyrimidine synthesis, its deficiency can lead to inhibited production of DNA, RNA. Also proteins synthesis is inhibited as tetrahydrofolate is involved in the synthesis of amino acids serine and methionine. ###### 1- Methotrexate It is also could be used in treatment of autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions (generally in combination with misoprostol). ###### 2- Pralatrexate ###### 3- Pemetrexed In addition, Pemetrexed inhibits other two enzymes used in purine and pyrimidine synthesis thymidylate synthase and glycinamide ribonucleotide formyltransferase. ### III) Antibiotic Anticancer agents #### i) Anthracycline antibiotics They are a class of drugs used in cancer chemotherapy derived from Streptomyces bacterium Streptomyces peucetius. The anthracyclines are among the most effective anticancer treatments ever developed and are effective against more types of cancer than any other class of chemotherapeutic agents. Their main adverse effect is Cardiotoxicity. ###### Mechanism of action Anthracycline has four mechanisms of action: 1. Inhibits DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells. 2. Inhibits topoisomerase II enzyme, preventing the relaxing of supercoiled DNA and thus blocking DNA transcription and replication. 3. Creates iron-mediated free oxygen radicals that damage the DNA, proteins and cell membranes. 4. Induces histone eviction from chromatin that deregulates DNA damage response, epigenome and transcriptome. ###### 1- Daunorubicin It is also known as Daunomycin. It was initially isolated from Streptomyces peucetius. ###### 2- Doxorubicin ###### 3- Idarubicin The absence of a methoxy group increases its fat solubility and cellular uptake. #### ii) Actinomycines antibiotics They are a class of polypeptide antibiotics isolated from soil bacteria of the genus Streptomyces. As one of the older chemotherapy drugs, it has been used for many years. ###### Mechanism of action They have the ability to inhibit transcription by binding DNA at the transcription initiation complex and preventing elongation of RNA chain by RNA polymerase. ###### Actinomycin D It is the most significant member of actinomycines. It is used in treatment of a variety of cancers. The common side effects include bone marrow suppression, fatigue, hair loss, mouth ulcer, loss of appetite and diarrhea. ###### iii- Mitomycin It is an aziridine-containing natural product isolated from Streptomyces caespitosus or Streptomyces lavendulae. It could be used for treatment of esophageal carcinoma, anal cancers, and breast cancers, as well as bladder tumaLLKO ###### Mechanism of action Mitomycin is a potent DNA crosslinker. This crosslinking is accomplished by reductive activation followed by two N-alkylations. Both alkylations are sequence specific for a guanine nucleoside. ### IV) Topoisomerase inhibitors Topoisomerase inhibitors are drugs that affect the activity of two enzymes; topoisomerase I and topoisomerase II. When the DNA double stranded helix is unwound, during DNA replication or translation for example, the adjacent unopened DNA winds tighter (supercoils), like opening the middle of a twisted rope. The stress caused by this effect is in part aided by the topoisomerase enzymes. They produce single or double strand breaks into DNA, reducing the tension in the DNA strand. This allows the normal unwinding of DNA to occur during replication or translation. Inhibition of topoisomerase I or II interferes with both of these processes. #### Topoisomerase I inhibitors ###### 1- Camptothecin It is a cytotoxic quinoline alkaloid. Due to severe adverse effects, synthestic analogs have been developed. CPT binds to the topo I and DNA complex. The most important part of the structure is the E-ring which interacts from three different positions with the enzyme. The hydroxyl group in position 20 forms hydrogen bond to the side chain on Asp533. It is critical that the configuration of the chiral carbon is (S) because (R) is inactive. The lactone is bonded with two hydrogen bonds to the amino groups on Arg364. The D-ring (carbonyl group in position 17) interacts with the +1 cytosine (amino group on the pyrimidine ring) on non-cleaved strand and stabilizes the topo I-DNA covalent complex by forming hydrogen bond. #### SAR * Substitution at position 7, 9, 10 and 11 enhance the activity. * Enlargement of the lactone ring by one carbon enhances the activity. * Substitution at position 12 and 14 leads to inactive derivatives. ###### 2- Topotecan It has FDA approval on October 15, 2007 as the first topoisomerase I inhibitor for oral use. ###### 3- Irinotecan #### Topoisomerase II inhibitors Drugs that target topoisomerase II can be divided into two groups. The topoisomerase II poisons cause increased levels enzymes bound to DNA. This prevents DNA replication and translation, causes DNA strand breaks, and leads to apoptosis (programmed cell death). Catalytic inhibitors, are drugs that block the activity of topoisomerase II, and therefore prevent DNA synthesis and translation because the DNA cannot unwind properly. ###### 1- Teniposide It is considered Topoisomerase II poisons. It is mainly used in the treatment of childhood acute lymphocytic leukemia. Adverse effects include severe myelosuppression gastrointestinal toxicity, hypersensitivity reactions, and alopecia. ### V) Anti-microtubule agents Anti-microtubule agents are plant-derived chemicals_that block cell division by preventing microtubule function. Microtubules are an important cellular structure composed of two proteins; a-tubulin_and ẞ-tubulin that are required for cell division, among other cellular functions. Microtubules are dynamic structures, which means that they are permanently in a state of assembly and disassembly. Vinca alkaloids and taxanes are the two main groups of anti-microtubule agents, and although both of these groups of drugs cause microtubule dysfunction, their mechanisms of action are completely opposite. #### i- Vinca alkaloids Vinca alkaloids are derived from the Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). They bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules. Following the success of these drugs, semi-synthetic vinca alkaloids were produced. ###### 1- Vincristine It is Natural Vinca alkaloid. The main uses are in non-Hodgkin's lymphoma as part of the chemotherapy combination. The main side-effects of vincristine are chemotherapy-induced peripheral neuropathy, hyponatremia, constipation, and hair loss. ###### 2- Vinorelbine It is Semisynthestic Vinca alkaloid #### ii- Taxanes Taxanes are diterpenes produced by the plants of the genus Taxus. Taxanes promote microtubule stability, and thus prevent microtubule disassembly. Taxanes are natural and semi-synthetic drugs. ###### 1- Paclitaxel It is a Natural Taxane. It is The first drug of this class. Paclitaxel is used for treatment of lung, ovarian, breast, head and neck cancer. The main side-effects include nausea and vomiting, loss of appetite, change in taste, thinned or brittle hair, severe exhaustion, skin rash, facial flushing, female infertility by ovarian damage and others. ### VI) Protein Kinase Inhibitors Protein kinases are enzymes which phosphorylate specific amino acids in protein substrates. In many cancers, it has been observed that there is an excess of growth hormone or growth factor of a particular protein kinase or protein kinase receptor. Since these structures are intimately involved in the signal transduction processes which drive cell growth and cell division. It is reasonable to assume that protein kinase inhibitors would be useful as anticancer agents. ###### 1- Gefitinib It is a kinase inhibitors of the epidermal growth factor receptor (EGFR). One of the two nitrogen atoms in the quinazoline ring interacts directly with Met-769, while the other interacts with a bridging water molecule which interacts with the hydroxyl group of Thr-830. The substituted aniline ring occupies a hydrophobic pocket. ###### 2- Imatinib It is an inhibitors of Abelson tyrosine kinase. The cancer cells involved contain an abnormal protein kinase which is not found in normal cells. An amino NH group is involved as a hydrogen bond donor to Met-318. If this group is alkylated, all activity is lost. The ortho-methyl group acts as a conformational blocker. It makes van der Waals interaction with the side chain of Leu-370. The piperazinyl group forms an ionic interaction with Glu-258. This interaction is important for selectivity. ### VII) Hormone-based Therapy Hormone-based therapies are used against cancers which are hormone dependent. If the cancer cell requires a specific hormone, then a hormone can be administered which has an opposing effect. Alternatively, hormone antagonists can be used to block the action of the required hormone. #### Avantages * Least toxic of anticancer drugs. * Highly selective. #### Uses Breast, endometrial, prostate cancers #### 1- Estrogens ###### MOA Inhibit the production of LH and thus, decrease the synthesis of testosterone. ###### Uses Treatment of prostate cancer. ###### Ethinylestradiol ###### Diethylstilesterol ###### Diethylstilbsterol diphosphate It is the diphosphate prodrug of diethylstilbestrol. It is only activated in target cells where it can reach higher concentrations than if the drug itself was administered (SELECTIVITY). #### 2- Progestins ###### MOA Inhibits secretion of pituitary gonadotropin. ###### Uses Treatment of advanced endometrial carcinoma and metastatic breast cancer. ###### Medroxy progesterone acetate ###### Megestrol acetate #### 3- Androgens ###### MOA Suppress production of LH resulting in decrease in estrogen synthesis. ###### Uses Treatment of metastatic breast cancer. ###### Fluoxymesterone ###### Testosterone propionate It is a prodrug which is converted to dihydrotestosterone (by hydrolysis of the ester group). #### 4- LHRH agonists ###### MOA On long term exposure to LHRH, the receptor becomes desensitized leading to a drop in LH level. Since LH stimulates the synthesis of testosterone, this results in lowered testosterone levels ###### Uses Treatment of advanced prostate cancer. ###### LHRH ###### Leuprolide ###### Goserelin Both are decapeptid NEARH designed to be more resistant to peptidase degradation. This normally takes place next to glycine at position 6, and replacing this amino acid with an unnatural D-amino acid makes this region unrecognizable to the enzyme. #### 5- Antiestrogens ###### Fulvestrant ###### MOA Steroidal estrogen antagonist that competes with estradiol for estrogen receptors in target breast cancer tissues. ###### Uses Treatment of hormone-dependent breast cancer. ###### Tamoxifen ###### Raloxifene ###### MOA They compete with estradiol for estrogen receptors in target breast tissues. ###### Uses Treatment of hormone-dependent breast cancer. #### 6- Antiandrogens ###### Cyproterone acetate ###### MOA It blocks the action of androgens at their receptors. ###### Uses Treatment of metastatic carcinoma of the prostate. ###### Flutamide ###### Nilutamide ###### MOA They act as selective antagonist of the androgen receptor (AR), preventing the effects of androgens like testosterone and dihydrotestosterone (DHT) in the body. ###### Uses Treatment of metastatic carcinoma of the prostate. ###### Metabolism ###### Flutamide ###### Hydroxyflutamide 10- to 25-fold higher affinity for the AR ###### Nilutamide ###### Hydroxynilutamide Same affinity to AR as Hydroxyflutamide #### 7- Aromatase inhibitors ###### Function of Aromatase ###### 17a-Hydroxyprogesterone ###### Androstenedione ###### Testosterone ###### Estrone ###### Estradiol ###### Uses Treatment of estrogen-dependent breast cancer. #### I) Reversible competitive inhibitors ###### Aminoglutethimide ###### Anastrazole ###### Letrozole The anilino nitrogen interacts with the haem iron of the aromatase and prevents binding of the steroid substrate. The N-4 nitrogen of the triazole ring serves the same purpose as the anilino nitrogen of glutethimide. #### II) Irreversible competitive inhibitors ###### Formestane (4-Hydroxyandrostenedione) ###### Exemestane It permanently inactivates aromatase and is more selective than Aminoglutethimide.