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Heterocyclic molecules as potential anti-cancer drugs

On November 28th, 2019, Posted by Lifesaver Essays

 Abstract

Cancer is one of the leading causes of death in developing countries. It causes severe physical, emotional and financial hardships on the afflicted and families. Biologically, the term “cancer” refers to uncontrolled growth of cells, in any part of the body, which results in a tumor. Cancer tumors can be benign or malignant. A cell becomes cancerous when its normal cell division control mechanisms go awry owing to mutation or some other genetic defect. Normal cells have tight regulation on their division and life span. i.e. After a certain period, they will get worn off and are replaced. But sometimes, these mechanisms get disturbed owing to some genetic or biochemical defects, as a result the normal controls of the cell cycle are absent and cells are lead into a continuous division phase. This proliferation, unless detected early and checked, progresses into cancer. Cancer when it is able to metastasize becomes seriously life threatening. A lot of research has been and is currently being pursued to identify many important genes and proteins involved in the cancer signalling pathway. Some important genes such as onco genes, tumor suppressor genes, p53, and angiogenesis promoting factors have been identified. Many approaches are being developed to combat cancer including chemotherapy, radiatherapy, gene therapy, transplantation as well as development of anti-cancer drugs. Anti cancer drugs include heterocyclic and aromatic, small molecules which are synthesised after studying probable structural interactions with the ligand (target molecule of interest)

In my project we are synthesizing a group of molecules which are structurally similar to the group of heterocyclic molecules called ellipticines.

Keywords: Cancer, anti-cancer drugs, heterocyclic compounds, ellipticines

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Introduction

Cancer

It is one of the world’s leading causes of death and particularly in developing countries.  As per WHO’s reports, almost 8.2 million people died from cancer in 2012. 60 % of new cancer cases arise in Asia, Africa and central and south America, so it is spreading. 30 % of cancers can be prevented. (World Health Organisation, 2014)

In terms of physical, mental, emotional and financial hardships, cancer can cause devastating damage and affliction on the patients and families of those who are suffering.

Causes of cancer

The term Cancer refers to a collection of diseases affecting different organs and tissues of the body, which arises out of the uncontrolled growth of abnormal cells.  This results in drastic changes in metabolism and normal bodily functions which impacts the quality of life and leads to death.  Abnormal cells, which have gone out of control are called cancerous cells. (National Cancer Institute, 2013)

(National Cancer Institute, n.d.)

Cells go into a cancerous state, when there is a failure in the normal cell division control mechanisms. cell division is tightly regulated process but under certain conditions the cells can go into an uncontrolled dividing state, an abnormal state, which if not recognised early, turns into cancer. The decision to divide or not is taken at the G1 phase of the interphase preceding cell division. What interferes with the normal state of affairs? Mutations in the genes involved in controlling and regulating the cell cycle pathway as well as known controllers of tumor and cancers such as onco genes and tumor repressors may lead to these effects.

What is the role of DNA in cell division and cancer? How DNA is affected by mutations and how does this lead to cancer?

The role of DNA is central to cell division and hence cancer development. The process of cell division occurs only so that the parental genetic material can be transferred to the offspring daughter cells and thus ensuring that the information inherent to DNA Is never lost. Hence an abnormality in cell division would imply an abnormality at some level in the structure/function of DNA. The structure of DNA or deoxyribonucleic acid is vital to its function i.e. expression of the information coded within it as well as its own replication. Therefore anything which is detrimental to the functioning of DNA (leading to cancer) is definitely bound to have an influence on DNA either at the chromosome organization level, prior to cell division or at the gene expression level.

DNA consists of two chains of nucleotides which are helically twisted around each other. Each nucleotide consists of a phosphosugar moiety attached to a base, which can be any of four ( Adenine, thymine, cytosine, guanine). The base pairing rules, which decides the way the strands are bound to each other, requires Adenine to pair with Thymine and Cytosine with Guanine. The nucleotide base pairs form the middle part of the helix.

DNA is organized into chromatin threads, which condense to form chromosomes at the time of cell division. DNA replication occurs prior to cell division during the Synthetic phase of the interphase. The doubled DNA later condenses to appear in the form of chromosomes. DNA replication involves several enzymes and proteins. The process requires the cutting and unwinding of the DNA helix by the action of enzymes such as DNA gyrases and helicases, creation of a replication fork by the action of proteins such as single stranded binding proteins, which helps to stabilize the fork formed and the action of the DNA polymerases, which creates new DNA threads using the parental template, based on the base pairing rules i.e. Adenine pairs with Thymine and Cytosine with Guanine. This process is bidirectional as owing to the directionality of the polymerase enzyme, one strand is read in reverse and the fragments have to be added up. The ligation of the DNA fragments is carried out by DNA Ligases and the new DNA daughter molecules are zipped back. Once the DNA molecules are formed, they have to be condensed into chromatin, to fit inside the new daughter cell nuclei. This is done by the aid of histones. Histones are basic proteins and provide the energy required for this process. 2 molecules each of histoneH2a, H2b, H3 and H4 and one molecule of H1 bind to 166 bp of Dna to form the nucleosom and this chain of nucleosomes joined by linker DNA  forms the chromatin. This “beads on a string: chromatin undergoes further condensation to form chromosomes. ( http://www.nature.com/scitable/topicpage/dna-packaging-nucleosomes-and-chromatin-310)

Transformation of DNA to chromosomes/chromatin is a dynamic process and needs to be a transiently reversible as many processes such as replication, transcription requires opening and closing up of the DNA, so that the enzymatic machinery involved can do their processes. Chromatin modeling for such purposes is carried out by modification of the histones by acetylation, methlyation or phosphorylation or by replacement by chromatin modeling complexes.

Because of the complexity of the DNA structure and its vitality for the survival, mutations at any point can severally create changes in DNA which may subsequently lead to cancer. Some kind of mutations which can cause changes to DNA chemically and structurally can be classified as

  1. Spontaneous mutations: These include changes in the chemical structure of the DNA molecule such as base changes due to tautomerism, depurination, deamination etc These may lead to point mutations, deletions, insertions and incorrect base pairing. Many mutations are introduced owing to errors in replication as a result of faulty proof reading activity of the enzymes. Repair of double stranded breaks in DNA Molecule can introduce mutations. Exposure to chemical agents can also induce mutatgenesis in the molecule. These include use of base analogs alkylating agents, cross linking agents, radiation etc.
  2. Structural mutations.- These introduce mutations at the chromosomal level and include amplification of chromosomal sequences, large deletions, chromosomal transpositions, translocations and insertions.

Many of these mutations can have drastic changes leading to gain or loss of function of the gene product, totally different products, truncated proteins, etc. Thus, mutations in any genes associated with cancer regulation, cell division, DNA replication and transcription can lead to high probability of occurrence of cancer.

What are the approaches to combating and managing cancer?

Worldwide, lot of effort has been spent in understanding the molecular mechanisms of cancer so that approaches could be developed in fighting and if possible taming this scourge. Some of the approaches include chemotherapy, radiation therapy, targeted therapies, transplantations as well as use of approaches like use of angiogenesis inhibitors, biological methods like gene therapy, and use of small molecules including anti cancer drugs.

Chemotherapy uses chemicals to attack and destroy cancer cells by either stopping or slowing their growth.  The side effects of this are that it can end up attacking the good cells in other parts of your body and you may feel extreme fatigue and tiredness. Chemotherapy can be used to cure, control and also reduce the symptoms of cancer. Many times chemotherapy is carried out along with surgery, radiation and biological therapy. Radiation therapy involves the killing of cancer cells by exposing their DNA to high energy radiation. Again, the risk is of killing the normal cells alongside the cancerous cells.

Targetted cancer therapies involve the use of anti cancer drugs and other substances which block the growth and spread of cancer by targeted specific molecules which are involved in the cancer biology. The targets are called molecular targets and the therapies are called molecular target therapies. Many of these anti cancer drugs act by interfering with

  1. cell growth signalling processes
  2. angiogenesis
  3. apoptosis of cancer cells
  4. Stimulation of immune system to recognise cancer cells and act on them

Hence the selection of good targets is necessary. Small molecule drugs act by diffusing across cell membrane and acting on target molecule. They are usually identified through screens of families of chemical molecules, by studying their effect on target of interest, drug-docking studies, crystallographic studies of the drug-molecule interaction  carrying out any required modifications and synthesising it for the phase trial studies.

There are different classes of small molecules used for anti cancer drug studies. Many of these are classified on the basis of their structure and action.

Mechanism of anti-cancer drugs on DNA

Chemotherapy and Anti cancer drugs can act on cancer by affecting the DNA of the cancer cells in the following ways:

  1. Damaging the DNA of the affected cancer cells
  2. Inhibiting the synthesis of DNA i.e. its replication and thus interfering with the cell proliferation.
  3. Stopping mitosis or the cell division itself and not allowing the cells to divide

(http://www.elmhurst.edu/~chm/vchembook/655cancer.html)

Anti cancer drugs which act on DNA can do so by

  1. interfering with the synthesis of nucleotides and thus interfering with replication. These drugs replace the normal nucleotides and thus get incorporated into new DNA chains leading to cell damage e.g. methotrexate, fluorouracil, hydroxyurea (http://www.elmhurst.edu/~chm/vchembook/655cancer.html)
  2. directly damage the DNA and affect replication and transcription e.g. cisplatin and different antibiotics. They include molecules which can act on the DNA as:
  3. groove binders- they bind to the grooves of the DNA helix.
  4. intercalating agents- they sit in between the base pairs of the helix and interfere with the action of topoisomerases causing DNA breakage, chromosomal damage
  5. alkylators- they directly alter the DNA molecule by chemically modifying it by alkylation. They include the nitrogen mustards, nitrosoureas, alkyl sulfonates, triazines and ethylenimines
  6. DNA cleavage agents- break the DNA molecule

iii. Inhibiting enzymes of replication- Anthracyclines are antibiotics which inhibit enzymes required for DNA replication. These include daunorubicin, doxorubicin

  1. Some interfere with the enzymes which keep the DNA strands apart during replication i.e. the topoisomerases. These include topoisomerase I and II inhibitors such as topotecan and etoposide.

(http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/chemotherapy/chemotherapyprinciplesanin-depthdiscussionofthetechniquesanditsroleintreatment/chemotherapy-principles-types-of-chemo-drugs)

V Mitotic inhibitors: plant alkaloids which interfere with the cell division

Heterocyclic compounds as anti-cancer drugs

Heterocyclic organic compounds are those which have some or all of their atoms as part of a ring with at least one atom other than carbon. They resemble cyclic organic compounds but the presence of hetero-atoms confers upon them different properties.

Heterocyclic compounds contain rings with carbon, nitrogen and sulfur atoms. These can be three, four, five and six-membered ring structures. Three and Four are usually intermediates in reactions while five and six are stabler and more aromatic. Some examples of these are: (Heterocyclic compounds, n.d.)

  1. Three membered heterocyclic compounds: aziridine, oxirane and thiirane. Formation of aziridine is one of the reactions involved in the action of anticancer drugs called nitrogen mustards. This includes mecholoethamine, cyclophosphamide and melphalan An aziridinium ion is the biologically active intermediate formed during the action of the anti cancer drug mechloroethamine, which acts on cancer cells by interfering with the DNA replications. Aziridine derivatives are also involved in the action of the mitomycin C family of anti tumour antibiotics. Some other three membered derivatives can also function as bactericidal agents.
  2. Four membered heterocylic molecules include penicillins and cephalosporins
  3. Five membered – pyrrole, furan and thiophene derivatives include chlorophylls, heme groups etc

(Kizek et al 2012)

Several heterocyclic compounds are being synthesized and tried out as anti cancer drugs. Examples are those which contains chromone scaffold as their pharmacophore, acridines, benzimidazoles,indoles etc. Their ringed structures confers freedom of rotation which allows them to fit into the minor grooves and bind (ATDBIO Ltd, 2014 ) with the DNA through hydrophobic and hydrogen bonding interactions.  The earliest known use of heterocyclic compounds as anti cancer drugs, were that of the nitrogen mustards, which has aziridine as one of the biologically active intermediate form. They were accidentally discovered during experimental modifications of sulphur mustard gas. Nitrogen and Oxygen containing heterocycles are more abundant than sulfur containing ones. Examples of the functional groups include: ethylene oxide, ethyleneimine, trimethylene oxide, furan, tetrahydrofuran, pyran, pyridine etc.

Role of nitrogen containing heterocyclic compounds as anti cancer drugs came into prominence with the discovery of nitrogen mustards. Nitrogen containing heterocycles such as  like indole, pyrimidine, pyridine and quinoline are targets of anti cancer drug synthesis as they can accept suitable subsituents at the C3 (indole), C5 (pyrimidine) C2 (pyridine) position. These sites possess the requirements for targeting multiple ligands viz possessing nitrogen and oxygen for ligating and hydrophobic groups. Research is being carried out in this direction. For e.g. many anti drugs have been synthesised which contains the indole ring as the pharmacophore e.g. vincristine ,vinblastine.

( http://www.sciipub.com/index.php/forum/4-international-journal-of-natural-product-science-issn-2249-6335/289-anti-cancer-activities-of-various-heterocyclic-containing-entites-a-review-gurvinder-kaur-and-rakesh-yadav) ( http://www.ajpcr.com/Vol5Issue1/593.pdf)

Ellipticines are a class of cytotoxic drugs which kills cancer cells at concentrations from 10-8 to 10-6 M. They belong to class of intercalators, which insert themselves between the base pairs of the DNA molecule. This DNA binding capacity is linked to their anti cancer activity. Ellipticine and 9 methoxyellipticine are obtained from plant extracts, of the Apocynaceae family. The molecules are characterised by a pyridocarbazide nucleus. Some members of the ellipticine family have also been shown to be involved in killing cancer cells by interfering with the expression of RNA polymerase I and demonstrates a very high specificity for it. Thus, the drug is believed to affect the formation of the pre initiation complex for transcription by not allowing the recognition of the rRNA promoter by the specific protein required for initiate of transcription. (Andrews et al 2013) Another important finding, which renders ellipticine such an important molecule of study  as an anti cancer drug is the fact that it has been found to induce apoptosis in human endometrial cancer cell lines presumable via formation of reactive oxygen species and MAP kinases.

Another cytotoxic drug is cryptolepine. It is an indoloquinoline alkaloid,which occurs naturally and has been used as an anti-malarial drug and has a wide variety of pharmacological effects. Cryptolepine acts as a DNA intercalator and it has been shown to bind to CG rich sequences interspersed with non alternating  CC regions through a base stacking interaction mode  and it inhibits DNA synthesis in melanoma cells  and is also a powerful topi II  inhibitor ( Lisgarten et al 2001) DNA intercalators function in two ways : either through perpendicular interactions with the base pairs ( at CG rich sequences with alternating purine-pyrimidine sequences) or through parallel interactions with the base pairs wherein the aromatic rings are stacked onto the Bases (both CG sequences with alternating and non alternating purine-pyrimidine sequences). Cryptolepine seems to be in the second category.

The study involves the creation go anti cancer drugs similar to the ellipticin family by creating heterocyclic derivatives using the reagent 1,2,3,4 tetrahydroisoquinoline. This is a secondary amine and its skeleton is the basis of drugs such as tubocurarine.

Aim

In this study, we attempted to create a group of compounds similar to the anti-cancer heterocyclic molecule family, the ellipticins. The synthesis of heterocyclic derivatives involved the reaction of the reagent 1,2,3,4 tetrahydroisoquinoline with various substrates and the derivatives were tested for anti-cancer activity by assays and other methods. (Kizek et al, 2012)

References

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Aktipis, C.A. and Nesse, R.M. (2013) Evolutionary foundations for cancer biologyEvol Appl. Vol 6. No.1. pp: 144–159.Evol Appl. 2013 January; 6(1): 144–159. doi:  10.1111/eva.12034

American Cancer Society, 2014. What is cancer? Retrieved from the American Cancer Society website : http://www.cancer.org/cancer/cancerbasics/what-is-cancer

Andrews, W.J., Panova, T., Normand, C., Gadal, O., Tikhonova, I.G. andPanov,  K.I. (2013)  Old drug, new target: ellipticines selectively inhibit RNA polymerase I transcription. Journal of Biological Chemistry.  Vol.15 No 288 pp:4567-82. doi: 10.1074/jbc.M112.411611.

ATDBIO Ltd, 2014. Nucleic Acid Drug Interactions. Retrieved from the ATDBIO website http://www.atdbio.com/content/16/Nucleic-acid-drug-interactions

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Hoelder, S., Clarke, P. A.,  and Workman, P. (2012) Discovery of small molecule cancer drugs: Successes, challenges and opportunities.  Molecular Oncology. Vol.6. no.2. pp:155-176 doi:  10.1016/j.molonc.2012.02.004

Kizek, R.,Adam, V., Hrabeta, J., Eckschlager,T., Smutny,S.,Burda, J.V., Frei, E., and Stiborova, M. (2012)  Anthracyclines and ellipticines as DNA-damaging anticancer drugs: Recent advances. Pharmacology and Therapeutics. Vol. 133, No.1, pp:26-39 http://dx.doi.org/10.1016/j.pharmthera.2011.07.006

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http://www.nature.com/scitable/topicpage/dna-packaging-nucleosomes-and-chromatin-310

http://www.ebi.ac.uk/interpro/potm/2006_1/Page2.htm

http://www.nature.com/nsmb/journal/v9/n1/full/nsb729.html

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