chapter: 1shodhganga.inflibnet.ac.in/bitstream/10603/54925/9/09... · 2018-07-03 · chapter: 1...

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JAYESH A. SHARMA, B. V. PATEL PERD CENTRE

CHAPTER-1: Intoduction

The drug discovery process is rapidly evolving due to technological development in

target identification along with automation of combinatorial synthesis and high

throughput screening (HTS). In light of these advances, improving efficiency in the

optimization of desired pharmacological activity in humans while decreasing the

reliance on animal studies has become a challenge.

The concepts of “target-rich, lead-poor” pipelines in drug discovery, and the grave

concern about the attrition rate of chemical compounds in (pre) clinical development,

are together fuelling the search for better quality hits and chemical lead series.

Researchers are rising to this challenge by devising ways to identify chemical leads for

specific targets. [1, 2]

Fig. 1.1: Drug development process (IND; investigational new drug, NDA: new drug

application).

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1.1: Introduction to Cancer

Cancer is one of the most important health problems of the current era and also a

leading cause of death. Cancer can simply be defined as unregulated cell division leading

to a tumor formation in any part of the body. In its natural course, tumor mass

continues to grow invading the surrounding tissues and finally tumor cells get access to

the lymphatic and vascular systems spreading to distant organs which results in

metastasis. In order to be successful in the treatment of cancer, early diagnosis, before

the tumor spreads to the surrounding tissues or distant organs, is mandatory.

Fig. 1.2: The 10 Hallmarks of Cancer. 1

Cancer is an uncontrolled cell growth anywhere in the body. It is characterized by “

unregulated proliferation of cells and caused by the loss of control over a cell's

proliferative capacity, rather than dividing in a controlled and programmed manner.

Because of these factors the cell continues to divide and multiply abnormally”. The

disturbing characteristics of cancer are (A) Self-sufficiency in growth factors, (B)

Insensitivity to anti-growth factor, (C) Evasion of apoptosis, (D) Tissue invasion (E)

Uncontrolled angiogenesis, (F) Altered metabolism, (G) Inflammation and (H) Genetic

alteration and instability. [3] The profiles of cancer reveal (a) DNA level defect -

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(b) Difference in gene expression (c) Protein expression. [4] More than 150 types of

cancer have been reported till date.

1.2: Cancer Statistics

In today’s era of globalization, incidences of different kinds of cancer are on the rise.

Cancers of the lung and bronchus, prostate, and colorectum in men, and cancers of the

lung and bronchus, breast, and colorectum in women continue to be the most common

causes of cancer related deaths. Currently, one in 4 deaths in the United States is due to

cancer. [5] A total of 15,96,670 new cancer cases and 5,71,950 deaths from cancer are

projected to occur in the United States in 2011. In 2012, 14.2 million new cancer cases

and 8.2 million cancers related death are estimated worldwide. [6] It is the second

major cause of deaths after cardiovascular diseases. Every year about 8, 50, 000 new

cancer cases are diagnosed in India resulting in about 5,80,000 cancer related death

every year. India has the highest number of the oral and throat cancer cases in the

world. Every third oral cancer patient in the world is from India. [7]

1.3: The link between cancer, inflammation and transcription factors like NF-kB and

AP-1.

Cancer is a complex set of diseases. [3, 4] Inflammation is a natural defence system or

response of the body which repairs injuries and lesions caused by pathogens or foreign

materials. Chronic-inflammation is prolonged duration process and is a risk factor for all

kinds of cancer is well known. The pro-inflammatory genes products have been

identified and chronic-inflammation plays a key role in the suppression of apoptotic

process, tumor genesis including cellular transformation, survival, proliferation,

invasion, angiogenesis and metastasis. The expression of these pro-inflammatory genes

products are mainly regulated by transcription factors nuclear factor kappa-light-chain-

enhancer (NF-kB) and activator protein-1(AP-1). [8, 9]

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1.3.1: Cancer and inflammation a hot link.

Virchow first noted in the 19th century that inflammatory cells are present within

tumors and that tumors arise at sites of chronic inflammation. [10] This inflammation is

now regarded as a “secret killer” for diseases such as cancer and other like inflammatory

bowel diseases such as Crown disease and ulcerative colitis which are associated with

increased risk of colon adenocarcinoma. [11-13] Chronic pancreatitis is related to an

increased rate of pancreatic cancer. [14]

Inflammation is a complex biological response needed in the protection or repair of the

body and it must be exquisitely regulated. In other words, inflammation is localized

protective reaction towards injury, irritation or infection characterized by pain, redness,

swelling or loss of functions. Inflammation is of two types acute and chronic. Acute

inflammation, the initial stage of inflammation, represents innate immunity; it is

mediated through the activation of the immune system, lasts for a short period and

generally is regarded as therapeutic inflammation. If the inflammation persists for a long

period of time, however, the second stage, chronic inflammation results. [15] Chronic

inflammation has been linked with most chronic illnesses, including cancer,

cardiovascular disease, diabetes, obesity, pulmonary disease, and neurologic

disease.[16] Only 5% to 10% of all cancers are caused by inheritance of mutated genes

and somatic mutations, whereas the remaining 90% to 95% have been linked to lifestyle

factors and environment. The underlying mechanisms by which these risk factors induce

cancer are becoming increasingly evident. One process that seems to be common to all

these risk factors is inflammation. [17]

Cytokines and chemokines are redundant secreted proteins with growth,

differentiation, and activation functions that regulate and determine the nature of

immune responses and control immune cell trafficking and the cellular arrangement of

immune organs. Cytokines [(interleukins ILs, tumor necrosis factor alpha (TNF-α)] and

chemokines plays an important role in a number of autoimmune diseases. The

transcription factor, NF-kB is essential for the transcriptional regulation of the

proinflammatory cytokines. Many examples are reported which involve the role of

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cytokines both in inflammation and cancer. Similarly lots of evidences have suggested

that there is a link between inflammation and cancer which involves the key role of

transcription factors like NF-kB and AP-1.

1.3.2: NF-kB pharmacology and its role in cancer

NF-κB and AP-1 are key transcription factors that regulate the expression of many genes

involved in inflammation, apoptosis, and oncogenesis. [18] Many reports have

demonstrated that these transcription factors are thought to be regulated by the same

intracellular signal transduction pathway. NF-κB signaling pathway plays a major role in

the development, maintenance, and progression of most chronic diseases. NF-κB

controls the expression of genes involved in a number of physiological responses,

including immune inflammatory responses, acute-phase inflammatory responses,

oxidative stress responses, cell adhesion, differentiation, and apoptosis.[19] Recent

studies have suggested that NF-κB dysregulation is associated with many diseases

including AIDS, atherosclerosis, asthma, arthritis, diabetes, inflammatory bowel disease,

stroke, muscle wasting and viral infections. There are many reports to suggest that NF-

κB acts as a link between inflammation and cancer progression. [20-23]

The activity of NF-κB is regulated by its interaction with the family of NF-κB inhibitor

known as IκB, which results in the formation of inactive NF-κB-IκB complex in the

cytoplasm. In response to various stimuli, IκB kinase (IKK) phosphorylates IκB. The

subsequent proteosome mediated degradation of IκB exposes the nuclear localization

signal of NF-κB, thus allowing its translocation to the nucleus where it activates the

transcription of various target genes [24, 25]. NF-κB activation occurs mainly through

canonical and non-canonical pathways, during the past decade a number of potential

target for inhibition for NF-κB activation pathways have been elucidated. Once in the

nucleus, activated NF-κB undergoes a series of posttranslational modifications, including

phosphorylation, acetylation, and methylation. These modifications regulate both the

strength and duration of NF-κB activity. RelA/p65 is directly phosphorylated by cAMP-

dependent protein kinase (PKA) at Ser-276, casein kinase II (CKII) at Ser- 529, and IKK at

Ser-536. [26, 27] RelA dephosphorylation by protein phosphatase 2A (PP2A) has been

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reported to decrease NF-κB activity.[28] Many anticancer and cytotoxic drug have been

reported to regulate NF-kB pathway. [29]

1.3.3: Activator protein-1 pharmacology and its role in cancer

Activator protein-1 (AP-1) is one of the first mammalian sequence-specific transcription

factor recognized. AP-1 was first known as a 12-O-tetradecanoyl phorbyl-13-acetate

(TPA) inducible transcription factor, since the TPA response element (TRE) was identified

as a binding site for AP-1 in many cellular and viral genes. The AP-1 transcription factor

is a dimeric complex that contains members of the JUN, FOS, ATF and MAF protein

families. AP-1 activity can be regulated by dimer composition, transcription, post-

translational modification and interactions with other proteins. The most common post

translational modification known to regulate protein activity is phosphorylation. AP-1

proteins are phosphorylated by MAPKs. Furthermore, AP-1 proteins are regulated by

ubiquitination, which targets proteins for proteosome-mediated degradation. Like other

transcription factors AP-1 regulates the inducible gene expression of interleukine-2 (IL-

2) and IL-3 genes. It also regulates GM-CSF production and production of matrix

metalloproteinases. AP-1 is a group of basic leucine zipper (b-ZIP) transcription factor

consisting of the c-Fos and c-Jun families. Extracellular stimuli and growth factor

stimulate MAPK pathways which play important role in regulation of transcription factor

AP-1, as its activation leads to the induction of c-Fos which associate to c-Jun to form an

AP-1 heteromeric complex that can promote target gene expression. [30, 60]

Modulation of these transcription factors could be a promising approach in the design

of inflammatory, auto-immune diseases and cancer. Inhibitors of these transcription

factors are useful in cancer while the stimulators/activators of these transcription

factors have been found to be promising radio protective agents.[61] A variety of

extracellular signals including tumor promoters, UV irradiations, growth factors,

cytokines, neurotransmitters and Ras oncoproteins stimulate AP-1 activity. AP-1 is

regulated on multiple levels. The expression of AP-1 proteins is regulated by controlling

the transcription of their genes. AP-1 function is also dependent on dimer composition

in the DNA binding complex. In addition, AP-1 proteins are regulated by post

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translational modifications like phosphorylation by MAPKs. Hence AP-1 activity is

stimulated by a complex network of signaling pathways that involves external signals

(for eg. growth factors) and mitogen-activated protein kinases (MAPKs) of the

extracellular-signal regulated kinase (ERK), p38 and JUN amino-terminal kinase (JNK)

families. In most disease conditions including autoimmune diseases and cancer it has

been noted that the activation of NF-kB can be directly co-related with the simultaneous

co-activation of AP-1 in the system. Hence in most of previously discussed disease

conditions, NF-kB activation is similarly mimicked by AP-1 activation. Like NF-kB we can

find several reports which suggest the role of AP-1 in many human diseases like cancer.

[62] AP-1 is activated by many of the factors (viral infection, oxidants, and antigens) that

are known to increase the inflammatory response. This activation in turn leads to the

coordinated expression of many genes that encode proteins (such as cytokines,

chemokines, adhesion molecules, and enzymes) involved in mediator synthesis and the

further amplification and perpetuation of the inflammatory response. Activation of AP-1

produces disease conditions like rheumatoid arthritis, atherogenesis, multiple sclerosis,

chronic inflammatory demyelinating polyradiculoneuritis, asthma, inflammatory bowel

disease, helicobacter pylori-associated gastritis and systemic inflammatory response

syndrome. AP-1 can exert its oncogenic or antioncogenic effects by regulating genes

involved in cell proliferation, differentiation, apoptosis, angiogenesis and tumor

invasion. Hence, AP-1 might prove to be a good target for anticancer therapy and could

be used as a double edged sword in tumorigenesis. [63]

1.4: Cancer Treatment

Modern medicine has made huge advances towards the treatment of cancer. There are

four main treatments used. Generally a combination of the treatments is given to

ensure that the patient receives the best outcome.

1.4.1: Surgery: Surgery was once considered to be the only option, and indeed can

completely ‘cure’ cancer by the removal of cancerous tissue. If the cancer has been

diagnosed early then surgery can be the most effective treatment; however the

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problem is metastasis and oncogenic stem cells. Nowadays tissue biopsies are essential

for diagnosis and surgery is carried out in 90% of cancer patients.

1.4.2: Radiotherapy: Radiation therapy can stop cell proliferation and disrupts atoms

within tumor cells. The cell DNA is damaged beyond repair. However the radiation can’t

distinguish between healthy and cancer cells – especially rapidly dividing cells such as

bone marrow and hair follicles so patients suffer from side-effects. Doses can be given

internally or externally and advances in technology mean that the radiation can be

targeted more precisely to the desired area increasing dose efficiency and diminishing

damage to healthy cells.

1.4.3: Biotherapy: The cancer is controlled by the body’s natural defence system.

Immunotherapy or biotherapy uses the body’s immune system to fight cancer. It is

designed to repair, stimulate or enhance the body’s immune response. The treatment

should stop, control, or suppress processes that permit cancer growth by making cancer

cells more recognizable, and therefore more susceptible, to destruction by the immune

system. Biotherapy can also block or reverse the process that changes a normal cell or a

pre-cancerous cell into a cancerous cell.

1.4.4: Chemotherapy: Chemicals are used to kill cancerous cells by damaging the cell

proteins or the cell DNA. The aim is to cause apoptosis (cell suicide). Cytotoxic drugs

such as antibiotics, antimitotics, hormones, antimetabolites, inorganic compounds and

alkylating agents are currently used as chemotherapeutic agents. Chemotherapy cannot

distinguish between healthy and cancerous cells so side effects are then experienced.

The era of chemotherapy began in the 1940s with the first uses of nitrogen mustards

and antifolate drugs. Cancer drug development since then has transformed from a low-

budget, government-supported research effort to a high-stakes, and multi-billion dollar

industry. The targeted-therapy revolution has arrived, but the principles and limitations

of chemotherapy discovered by the early researchers still apply. Of the many challenges

of medicine, none has had a more controversial beginning and none has experienced

more hard-fought progress than the treatment and cure of cancer. Although the

neoplastic process has been recognized for centuries, little was known about the

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biological mechanisms of transformation and tumor progression until the advent of

molecular medicine in the latter half of the twentieth century. Before 1950, therapy

remained largely the province of the surgeon. Radiation therapy became a valuable tool

for control of local and regional disease after 1960, with the invention of the linear

accelerator, but, like surgery, could not eradicate metastatic cancer. Effective treatment

for most patients needed to reach every organ in the body. Drugs, biological molecules

and immune mediated therapies have therefore become the focus for current efforts to

cure cancer. From the first experiments with nitrogen mustard 60 years ago to current

attempts to develop drugs for specific cancer-related targets, researchers from multiple

disciplines have joined together in the search for more effective cancer drugs. Over

time, the development of anticancer therapies, based at first on empirical observations,

has become increasingly dependent on an understanding of human tumor biology. [64]

1.5: Small heterocycles and drug discovery programs.

Small heterocyclic scaffolds are present in more than 50% of pharmaceutical substances

and allow various interactions with the biological targets due to the presence of side

chains or various polar bonds, which are not accessible in carbocyclic scaffolds. The

assembly of various structural fragments to the heterocyclic molecular scaffold can

provide a facile framework to bind with the macromolecular targets. Five member

heterocycles in particular have proved to be the productive and popular in the design of

drugs. These rings can pack a relatively large numbers of polarized bonds in a relatively

small molecular space and also offer a convenient framework to which necessary side

chains can be attached.[65] The examples of small heterocyclic molecules as marketed

drugs include lipid lowering Atorvastatin, aromatase inhibitor for breast cancer

Letrozole, antifungal Fluconazole, anti-diabetic Rosiglitazone, Angiotensin antagonist

Losartan, ACE inhibitor Fosinopril, calcium channel blocker Nifedipine, cholesterol

absorption inhibitor Ezetimibe are few of them.[66]

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Fig. 1.3: Small heterocycles as drug in the market.

1.5.1: Small-molecule agents for cancer therapy

Receptor tyrosine kinases (RTKS) and non-RTKs are crucial mediators in signaling

pathways of cell proliferation, differentiation, migration, angiogenesis, cell-cycle

regulation and others, [67-69] and many are deregulated during tumorigenesis. Small-

molecule inhibitors target these kinases by direct effects on tumour cells, rather than by

causing immune responses as mAbs do. Most small-molecule inhibitors of tyrosine

kinases are ATP mimetics. Imatinib mesylate (Glivec), one of the first successful small-

molecule inhibitors, inactivates the kinase activity of the BCR–ABL fusion protein in CML

[70-71]. It has shown remarkable efficacy for the treatment of patients with Philadelphia

chromosome-positive CML. [72] It is also a multi-targeted inhibitor of other tyrosine

kinases, which is key to the pathogenesis of metastatic GISTs, and the platelet-derived

growth factor receptors PDGFRα and PDGFRβ, which are key to the pathogenesis of

PDGF-driven tumours such as glioblastoma and dermatofibrosarcoma protuberans. [73]

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Epidermal Growth Factor Receptor is also a rational target for small-molecule inhibitors.

[74]. Gefitinib (Iressa) and erlotinib (Tarceva) selectively inhibit EGFR, and both are

efficacious against EGFR-expressing cancers such as Non-Small-Cell-Lung

Carcinoma(NSCLC) and Head and Neck Squamous-Cell Carcinoma (HNSCC) Phase II

studies of these agents have also shown their efficacy with or without concurrent

chemotherapy in HNSCC, and several phase III trials of gefitinib are ongoing. [75]

Erlotinib in combination with an antimetabolite, gemcitabine, is also approved for

treating advanced pancreatic cancer.

Unlike monoclonal antibody (mAbs), small-molecule agents can translocate through

plasma membranes and interact with the cytoplasmic domain of cell-surface receptors

and intracellular signalling molecules. Therefore, various small-molecule inhibitors have

been generated to target cancer-cell proliferation and survival by inhibiting Ras

prenylation, Raf–MEK kinase, [76] phosphatidylinositol 3-kinase (PI3K), the mammalian

target of rapamycin (mTOR) pathway or heat shock protein 90 (HSP90), [77] cancer-cell

adhesion and invasion by inhibiting SRC kinase [78] or matrix metalloproteinases

(MMPs) [79] or neovascularization by inhibiting the vascular endothelial growth factor

RTK (VEGFR).

As a new type of small-molecule agent, sorafenib (Nexavar) is known to exert its

inhibitory effect on not only different isoforms of Raf serine kinase but also various RTKs

such as VEGFR, EGFR and PDGFR. [80] This dual-action kinase inihibitor shows broad-

spectrum antitumour activity by inhibiting tumour proliferation and angiogenesis. [81]

Another new anti-angiogenesis small molecule drug, sunitinib malate (Sutent), is also a

multitargeted tyrosine kinase inhibitor of VEGFR, PDGFR, KIT and Fms-like tyrosine

kinase 3 (FLT3). [82]Potential targets for the development of small-molecule agents

have also been identified in the ubiquitin–proteasome cycle arrest and apoptosis.

Bortezomib (Velcade), which was first developed as a selective, reversible inhibitor of

the chymotryptic protease in the 26S proteasome, has been reported to be effective

against various cancers, particularly haematological malignancies

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Recently small heterocycles like thiophene and thiazole derivatives developed at the

Department of Medicinal Chemistry, PERD centre, Ahmedabad have been found to be

effective as anti-inflammatory and anti-cancer agents [83-85] targeting transcription

factors and also adenosine receptors involved in asthma and COPD diseases. Synthetic

sophistication has increased to an impressive level since the last two centuries. Ongoing

development of novel synthetic concepts and methodologies has opened up the new

ways for the construction of many complex and challenging synthetic targets.

Fig. 1.4: Small heterocycles synthesized in PERD Centre.

In addition to this, one of the major tasks facing the pharmaceutical industry is

improving the efficiency of its explorative research. The development of chemical

compounds with desired biological properties is time-consuming and expensive. The

application of combinatorial compound libraries plays nowadays an important role for

reaching this goal and multi-component reactions (MCRs) are viewed as ideal tools to

assemble large compound libraries for medicinal purposes.[86-89] By minimizing the

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number of synthetic operations while maximizing the buildup of structural and

functional complexity, these reactions are particularly appealing in this context.

1.6: Conclusion

Cancer will be soon global problem with its entire consecutive burden and there is a

great need to find out the compounds show efficacious activity without the undesired

side effects. The above mentioned evidences suggest that small heterocyclic compounds

are importante in the drug discovery process and have biological importance in

physiology of cancer also.

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