AN OVERVIEW OF QUINOLINE DERIVATIVES AS ANTI-CANCER AGENTS

: One of the most significant pharmacophoric cores in drug discovery in recent decades, notably in anticancer research, has been the quinoline scaffold. Many lead compounds with promising selective cytotoxic and immunomodulatory properties are discovered using quinoline derivatives. The review of the literature found that quinoline derivatives have the ability to inhibit protein kinases and other molecular targets. It was also designed to be involved in the disruption of tubulin assembly. The purpose of this review is to highlight findings from studies on quinoline compounds that demonstrate several anticancer pathways.‎ Overall, the design, discovery, and development of novel and potential multi-target anticancer agents or drugs may benefit from this class of quinoline molecules.


Introduction
The cancer develops from a single cell in which the normal mechanisms for control of growth and proliferation are altered.There are substances known to have carcinogenic risks, including chemicals, environmental factors, and viruses.Environmental factors, such as excessive sun exposure, can result in skin cancer, and smoking is widely known as a cause of lung cancer.Viruses, including human papilloma virus (HPV), Epstein-Barr virus, and hepatitis B virus, have been linked to cervical cancers, lymphomas, and liver cancers, respectively (Chisholm-Burns et al., 2013).There are two major classes of genes involved in carcinogenesis (oncogenes) as Ras gene and tumor suppressor genes (anti-oncogene) as p53.If they are mutated, this disrupts the normal cellular function and the cell can become cancerous (Patrick, 2005).
Quinoline is a versatile pharmacophore, a privileged scaffold, and an outstanding fused heterocyclic molecule with numerous activities, including anticancer, anti-inflammatory, antibacterial, and antiviral compounds.Quinoline hybrids have already demonstrated outstanding results as an inhibitor of cell proliferation via many modes of actions including cell cycle arrest, death, angiogenesis, disruption of cell migration, and modulation (Yadav & Shah , 2021).The study of natural molecules is what sparked interest in quinoline derivatives as bioactive compounds (Marciniec et al., 2023).

Quinine (1)
Quinine (1) is an antimalarial alkaloid which is extracted from the bark of the cinchona tree.Interestingly, the reports in the contemporary literature describe the anti-cancer activity of Quinine in relation to breast cancer cells MCF-7 (Martirosyan et al., 2004).

Streptonigrin (5) Lavendamycin (6)
Streptonigrin (5) is an aminoquinone alkaloid isolated from Streptomyces locculus and is gaining attention as a drug molecule owing to its potential antitumor and antibiotic effects.It was previously used as an anticancer drug but has been discontinued because of its toxic effects (Nasir et al., 2023).Furthermore, lavendamycin (6) is a naturally occurring chemical compound with anti-proliferative effects against several cancer cell lines.It was discovered in fermentation broth of the soil bacterium Streptomyces lavendulae (Hassani et al., 2008).

Anticancer activity and molecular targets of quinolines:
Quinoline hybrids have already demonstrated outstanding results as an inhibitor of cell proliferation via many modes of actions including cell cycle arrest, death, angiogenesis, disruption of cell migration, and modulation through targeting a variety of receptors and enzymes.

Protein Kinase inhibitors:
The protein kinase inhibitors have been among the most successful of the targeted anticancer drugs.Protein Kinases are a group of enzymes that are responsible for protein phosphorylation.These kinases' activity is crucial for fundamental processes, including cell cycle regulation, proliferation, differentiation, motility, and apoptosis.In tumor cells, it is frequently observed that key protein kinases are not appropriately regulated, leading to excessive phosphorylation and prolonged activation of signal transduction pathways (Dancey et al., 2003).
In mammalian signaling systems there are distinct classes of kinases that are classified by their substrate preferences:

Quinolines as Cyclin-Dependent Kinases (CDKs) inhibitors:
Cyclin-dependent kinases (CDKs) are critical regulators of cell cycle progression and RNA transcription.CDKs are activated by complexation with a group of associated proteins called cyclins.A variety of genetic and epigenetic events cause universal over activity of the cell cycle CDKs in human cancer, and their inhibition can lead to both cell cycle arrest and apoptosis.Apoptosis is a normal process that ensures equilibrium between cell proliferation and cell death and plays a regulatory role in controlling the size of cell populations as well as in tissues homeostasis.Inadequate or abnormal inhibition of apoptosis leads to unchecked cell proliferation resulting in cell accumulation and is considered as a hallmark of cancer (Shapiro et al., 2006).

RO-3306 (7)
RO-3306 (7) is a quinolinyl thiazolinone derivative, showed good potency, in vitro selectivity, and a cell cycle profile (G2/M arrest) consistent with CDK1 inhibition (Vassilev et al., 2006).In 2023, a series of quinones derivatives with morpholin alkylamino side chains was designed, synthesized and screened for the cytotoxic activity.The 6-isomer of 5,8-quinolinedione derivatives compound 8 possessed a potent antiproliferative activity, with IC 50 values of 0.59 μM (DLD1) and 0.44 μM (HCT116).It also resulted in a remarkable effect on cell cycle progression, blocking S-phase progression in DLD1 cells straight away while slowing S-phase progression and accumulated cells in the G2/M phase in HCT116 cells (Narwanti et al., 2023).

Quinolines as Phosphoinositide 3-kinases (PI3Ks) inhibitors:
The family of Phosphoinositide 3-kinases (PI3Ks) has been discovered to have crucial regulatory functions in various cellular processes including growth and proliferation, differentiation, survival, metabolism, and migration (Liu et al., 2009).The activation of the serine/threonine kinase Akt, also known as protein kinase B, occurs when PI3Ks translate signals from different growth factors and cytokines into intracellular messages.The PI3K signaling pathway, which is regulated by the tumor suppressor phosphatase and tensin homologue (PTEN), is crucially involved in this process (Song et al., 2012).

AMG-319 (9)
AMG-319 (9) was developed by Amgen as an anti-inflammatory drug with potential applications in the treatment of autoimmune conditions, but subsequent research revealed that it inhibits cell proliferation with promising anti-cancer effects with inhibition activity on the phosphoinositide 3-kinase enzyme subtype PI3Kδ (Cushing et al., 2015).

Quinolines as Aurora Kinase (AURK) inhibitors:
Aurora kinases (AURKs) were identified as promising targets for targeted cancer therapy.Overexpression of aurora kinases can cause disruption in the process of mitosis, resulting in genetic instability and the potential growth of tumors (Goldenson et al., 2015).(10) In 2020, Al-Sanea et al. designed and synthesized three series of 4-anilinoquinoline derivatives bearing a sulfonamide moiety.The assay of AURKA/B inhibition was determined for all target quinolines showed more than fifty percent inhibition on either of the enzymes, were evaluated further for their IC 50 on the corresponding enzyme.In particular, compound 10 displayed potent AURKA/B inhibitory activities with IC 50 of 0.93 and 0.09 µM, respectively (Al-Sanea et al., 2020).

Quinolines as Mitogen-activated protein kinases (MAPKs) inhibitors:
The MAPKs are vital components of serine/threonine protein kinase signaling pathways in cells that are responsible for responding to extracellular stimuli and regulating important cellular functions like proliferation, differentiation, and programmed cell death (apoptosis).The MAPK family can be divided into three main groups: a) p38 protein kinase b) c-jun N-terminal kinase (JNK) c) extracellular signal-regulated protein kinase (ERK) (Ravez et al., 2015).

Quinolines as RAF Kinase inhibitors:
Rapidly Accelerated Fibrosarcoma kinases (RAF kinases) participate in the RAS-RAF-MEK-ERK signal transduction cascade.This cascade participates in the regulation of a large variety of processes including apoptosis, cell cycle progression, differentiation, proliferation, and transformation to the cancerous state.RAS mutations occur in 15-30% of all human cancers, and B-RAF mutations occur in 30-60% of melanomas, 30-50% of thyroid cancers, and 5-20% of colorectal cancers.The three RAF kinase family members are A-RAF, B-RAF, and C-Raf (Roskoski et al., 2010).
In 2014, El-Gamal et al. reported a series of diarylamides possessing 6,7dimethoxy(dihydroxy)quinoline scaffold that showed antiproliferative activities against NCI-58 human cancer cell lines of nine different cancer types were tested.Compounds 13 showed the highest potencies.It revealed inhibitory effect against C-RAF kinase (76.65% at 10 μM) (El-Gamal et al., 2014).Moreover, El-Damasy et al. designed and synthesized a series of 2-amido and ureido quinoline derivatives substituted with 2-N-methylamidopyridin-4-yloxy group at the 5-position of quinoline as anticancer sorafenib congeners.Compound 14 was screened over a panel of 41 oncogenic kinases at a single dose concentration of 10 mM to profile its kinase inhibitory activity.Interestingly, this compound showed highly selective inhibitory activities (81.8% and 96.3%) against B-RAF V600E and C-RAF kinases with IC 50 values of 316 nM and 61 nM, respectively (El-

Tyrosine specific kinases:
Tyrosine kinases (TKs) catalyze selective phosphorylation of tyrosine residues in target proteins.This covalent post-translational modification is a significant component of signal transduction process, leading to cell proliferation, differentiation, migration, metabolism and apoptosis (Hunter et al., 2000).Tyrosine kinases are primarily classified as:

Quinolines as EGFR inhibitors
The EGFRs are responsible for overgrowth and proliferation of epidermal cells.The abnormal signaling of these pathways results in deregulated cell proliferation, evasion from apoptosis, angiogenesis, migration, and metastasis of cancer cells (Abhold et al., 2012).There are four categories of transmembrane receptors called EGFR receptors (also known as HER): HER-1, HER-2, HER-3, and HER-4].They are recognized as significant biological targets in different types of cancer tumors (Maennling et al., 2019).

Pelitinib (17)
Neratinib ( 18) Pyrotinib ( 19) Pelitinib (EKB-569) ( 17) is an irreversible epidermal growth factor receptor tyrosine kinase inhibitor that is used in clinical trials for colorectal and lung cancers (Lee et al., 2023).Furthermore, in 2011, neratinib (Nerlynx®) (18) was discovered and initially developed by Wyeth Pfizer as an orally available irreversible inhibitor of both the receptor tyrosine kinases (RTKs) human epidermal growth factor receptor 2 (HER2; ERBB2) and human epidermal growth factor receptor (EGFR), with potential antineoplastic activity (Blair et al., 2018) Some of reported 5-chloroquinolin-8-ol derivatives were synthesized and screened for their in vitro cytotoxicity towards three human cancer cell lines including MCF-7, A549 and HepG2.They were more potent than the reference erlotinib.Moreover, tyrosine kinase EGFR inhibition assay for the compounds revealed that compound 23 has triple inhibiting power with IC 50 value of 0.14 μM and compound 24 has nearly double inhibiting power with IC 50 value of 0.22 μM compared to erlotinib (Mamidala et al., 2022).Other quinoline analogues of substituted amide and sulphonamide derivatives were designed synthesized and were evaluated against five cell lines.Compound 25 exhibited promising inhibitory enzymatic activity against the EGFR L858R/T790M with IC 50 value of 138 nM, compared to Osimertinib's 110 nM (Kardile et al., 2023).

Quinolines as VEGFR inhibitors:
The over-activity of VEGFR-2 receptors was reported in the cancer cells versus the normal cells.This fact enabled researchers to target them therapeutically to produce safe and selective drugs that tackle angiogenesis in tumor cells with no activity on normal cells.The strategy to hinder the VEGF pathway is carried out by blocking the VEGFR-2 receptors activation using VEGFR-2 inhibitors (Elkaeed et al., 2022).

Lucitanib (28)
Tivozanib (29) Lucitanib 28, which is naphthalene-1-carboxamide derivative of quinoline, revealed potent activity inhibiting human vascular endothelial growth factor receptors (VEGFRs) and fibroblast growth factor receptors (FGFRs) with antiangiogenic activity nanomolar range, which may result in the inhibition of tumor angiogenesis and tumor cell proliferation, and the induction of tumor cell death (Soria et al., 2014).Additionally, tivozanib 29 (Fotivda®), a quinoline urea derivative, is a potent VEGFR inhibitor and received FDA approval in 2021 as a kinase inhibitor recommended for adult patients with relapsed or refractory advanced renal cell carcinoma (Caquelin et al., 2022).

Anlotinib (30)
Anlotinib 30 (AL3818) is an oral multitarget tyrosine kinase inhibitor that exerts its inhibitory effects on tumor growth and angiogenesis by targeting VEGFR-2, −3, FGFR1-4, PDGFR-α and -β, c-Kit and Ret.It was approved and launched in China in 2018 as a thirdline treatment for patients with refractory advanced NSCLC after more than 2 lines of systemic chemotherapy (Gao et al., 2020).

Quinolines as PDGFR inhibitors
Platelet-derived growth factor receptor (PDGFR) is a specific type of receptor found on the cell surface.It plays a crucial role in regulating cell proliferation, growth, and differentiation.However, when PDGFR becomes hyperactive, it can lead to uncontrolled cellular growth, ultimately contributing to various diseases such as pulmonary fibrosis, restenosis, and cancer.(Andrae et al., 2008).

Quinolines as C-Met inhibitors:
C-Met protein is a transmembrane tyrosine kinase that binds the hepatic growth factor (HGF) and plays an important role in the ability to activate a wide range of different cellular signaling pathways, including those involved in proliferation, motility, migration and invasion.(Organ et al., 2011).

AMG-208 (35) Foretinib (36)
AMG-208 ( 35) is a small-molecule MET inhibitor with IC 50 against wild type MET of 5.2 nM.At higher concentrations, AMG 208 inhibited other kinases, such as VEGFR2 with IC 50 = 112 nM.It suppressed proliferation and induced apoptosis in human tumor xenograft models (Hong et al., 2015).Foretinib 36 (GSK1363089) is an experimental c-Met and VEGFR-2 inhibitor.It is a drug candidate for the treatment of cancer was discovered by Exelixis and is under development by GlaxoSmithKline (Kim et al., 2022). (37) A study reported two novel series of 6,7-disubstitued-4-(2-fluorophenoxy)quinoline derivatives containing a-acyloxycarboxamide or a-acylaminoamide scaffolds were designed, synthesized, and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines Most of the target compounds showed moderate to potent and possessed selectivity for H460 and HT-29 cancer cell lines.Among these compounds, compound 37 (c-Met IC 50 = 2.43 nM) exhibited the most potent inhibitory activities against H460, HT-29 and MDA-MB-231 cell lines with IC 50 values of about 1.7-, 1.3-and 1.6-fold more active than foretinib, respectively (Nan et al., 2020).

BCR-Abl TK as a target for cancer treatment:
Chronic myeloid leukaemia (CML) is associated with the exchange of genetic material between the chromosomes 9 and 22, whereby the latter is altered and becomes the socalled Philadelphia chromosome.This transfer leads to a hybrid gene (bcr-abl), formed by transfer of one of the normal genes.This hybrid has deregulated and high ABL kinase activity, resulting in a high leukocyte count (Manley et al., 2005).

Bosutinib (38)
Bosutinib 38 (Bosulif®) is a Bcr-Abl kinase inhibitor.It is also an inhibitor of Src-family kinases including Src, Lyn, and Hck.The FDA approved the use of Bosutinib to treat patients with chronic, accelerated, or blast-phase Philadelphia chromosome-positive chronic myelogenous leukemia (CML) who are resistant to or cannot tolerate other therapies, such as imatinib (Cortes et al., 2018).

Quinolines as JAK inhibitors:
Janus kinase (JAK) is a family of intracellular that transduces cytokine-mediated signals via the JAK-STAT pathway which is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumor formation.The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through the process of transcription (Kiu et al., 2012).

Quinolines as tubulin inhibitors:
Microtubules have key roles in essential cellular processes such as mitosis, cell motion, and intracellular organelle transport.Microtubule inhibitors work by stopping or slowing down cell division and movement, and then it can stop or slow down the spread of cancer cells.The colchicine binding site is one of the most important pockets for potential tubulin polymerization destabilizers.Colchicine binding site inhibitors (CBSI) exert their biological effects by inhibiting tubulin assembly and suppressing microtubule formation (Lu et al., 2012).
Based on the structure of combretastatin A-4 (40), a series of quinoline derivatives incorporating rigid hydrazone and cyclic oxadiazole linkers were designed and synthesized.They demonstrated potent tubulin polymerization inhibitory properties and many of the novel derivatives showed significant antiproliferative activities in the submicromolar range.
The most potent compound (41) demonstrated superior with IC 50 values range (0.02-0.04 µM) against four cancer cell lines while maintaining low cytotoxicity in non-cancer cells as well as it inhibited tubulin polymerization (Ibrahim et al., 2020).
A series of quinoline derivatives were designed and synthesized as novel tubulin inhibitors targeting the colchicine binding site.Among them, compound 42 exhibited the highest antiproliferative activity with an IC 50 of 261 nM against HepG-2 cells.Mechanism studies revealed that compound 42 effectively inhibited tubulin polymerization in vitro and disrupted microtubule dynamics in HepG-2 cells (Ren et al., 2021).Furthermore, based on the pharmacophoric features of the colchicine binding site, a number of novel quinoline derivatives were designed to possess tubulin inhibitory activity.The most potent tubulin polymerization inhibitory affect was demonstrated by compounds 43 and 44, with IC 50 values of 9.11 and 10.5 nM, respectively compared to those of CA-4 (IC 50 = 13.2 nM) and colchicine (IC 50 = 10.6 nM) (Hagras et al., 2021).

Quinolines as topoisomerase inhibitors:
Topoisomerases (TOPs) are nuclear enzymes that play crucial roles in DNA replication, transcription, chromosome segregation, and recombination.All cells have two major forms (topoisomerase I and topoisomerase II).DNA topoisomerases are important targets of approved and experimental anti-cancer agents (Nitiss et al., 2012).The camptothecins including camptothecin (2), topotecan (3) and irinotecan ( 4) are examples of approved quinoline anticancer drugs and drug candidates with topoisomerases I inhibitory activity (Venditto et al., 2010).
(45) Two series of 4-alkoxy-2-arylquinolines were designed and synthesized as an attempt to develop potential anticancer agents targeting topoisomerase I.The compounds were screened for in vitro cytotoxic activity and the Compound 45 the most potent against colon cancer, leukemia and melanoma with GI 50 MG-MID 0.875, 0.904 and 0.926 μM, respectively (Elbadawi et al., 2021).

Quinolines as PARP inhibitors:
PARP (poly (ADP-ribose) polymerase) (PARP) inhibitors are a novel type of medications that works by preventing cancer cells from repairing their DNA once they have been damaged by other chemotherapy agents (Wiggans et al., 2015).

Talazoparib (46)
Talazoparib 46 (Talzenna®) is an orally available PARP inhibitor developed by Pfizer for the treatment of advanced breast cancer with germline BRCA mutations.It was approved in 2018, in the United States and 2019, in the EU for germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer (Hoy et al., 2018).

Quinolines as HDAC6 inhibitors
Histone deacetylase 6 (HDAC6) is an enzyme that in humans is encoded by the HDAC6 gene.HDAC6 has emerged as a highly promising candidate to selectively inhibit as a therapeutic strategy to combat several types of cancer and neurodegenerative disorders.HDAC6 is a unique member of the HDAC family that not only participates in histone acetylation and deacetylation but also targets several nonhistone substrates, such as α-tubulin, cortactin, and heat shock protein 90 (HSP90), to regulate cell proliferation, metastasis, invasion, and mitosis in tumors (Li et al., 2018).
(47a,b) 47a: R=H, X=CH, 47b: R=CH 3 , X=N A set of quinolone compounds were investigated in cellular studies to evaluate their anticancer effect against colon (HCT-116) and histiocytic lymphoma (U9347) cancer cells, showing good to excellent potency, leading to tumor cell death by apoptosis induction.The small molecules 47a, b were able to strongly inhibit the cytoplasmic and slightly the nuclear HDAC enzymes, increasing the acetylation of tubulin and of the lysine 9 and 14 of histone 3, respectively (Relitti et al., 2021).

Quinolines as HSP90 inhibitors:
The mammalian heat shock protein (HSP90) family of proteins is a group of highly conserved molecules that are involved in myriad cellular processes.HSP90 contributes in crucial physiological processes such as cell survival, cell cycle control, hormone signaling, and apoptosis.Conversely, HSP90, and its secreted forms, are included in the development and progress of serious pathologies, including cancer and neurodegenerative diseases.Therefore, targeting HSP90 is an attractive strategy for the treatment of neoplasms and other diseases (Hoter et al., 2018).
In 2019, Nepali et al. reported a study including the design and synthesis of amide tethered quinoline-resorcinol hybrid constructs as a new class of HSP90 inhibitor.In vitro studies of the synthetic compounds led to the identification of compound 48, which possesses potent cell growth inhibitory effects against HCT116, Hep3B and PC-3 cell lines, exerted through HSP90 inhibition.It triggers degradation of HSP90 client proteins along with concomitant induction of HSP70, demonstrates apoptosis inducing ability and causes G2M phase cell cycle arrest in PC-3 cells (Nepali et al., 2019).Additionally, a recent study reported that the quinolone derivative 49 was also able to increase Hsp90 acetylation levels in HCT-116 cells.(Relitti et al., 2021).

Quinolines as FTase inhibitors:
Farnesyltransferase (FTase) is a cytosolic metalloenzyme that catalyzes the transfer of a 15-carbon farnesyl lipid moiety to a group of cellular proteins characterized by a Cterminal CAAX motif.FTase inhibitors block the activity of the FTase enzyme by inhibiting prenylation of the CAAX tail motif, which ultimately prevents Ras from binding to the membrane, rendering it inactive which is critical to cell cycle progression.For this reason, several FTase inhibitors are undergoing testing as anti-cancer agents (Sebti et al., 2005).

Quinolines as PKM inhibitors:
Pyruvate kinase muscle isozyme (PKM), is an enzyme that in humans is encoded by the PKM2 gene.PKM2 can be aggregated into tetrameric and dimeric forms, PKM2 in the dimer state can enter the nuclear to regulate gene expression, and the transformation between them, so it can play an important role in tumor cell energy supply, epithelialmesenchymal transition (EMT), invasion and metastasis and cell proliferation (Zhang et al., 2019).In 2023, Marciniec et al reported that a series of 8-quinolinesulfonamide derivatives of PKM2 modulators were designed using molecular docking and molecular dynamics techniques.The results obtained from in vitro experiments confirmed the ability of compound 51 to reduce the intracellular pyruvate level in A549 lung cancer cells with simultaneous impact on cancer cell viability and cell-cycle phase distribution (Marciniec et al., 2023).

Quinolines as Carbonic anhydrase inhibitors:
Human carbonic anhydrases (EC 4.2.1.1)IX (hCA IX) and XII (hCA XII) are two tumor-associated proteins, being overexpressed in many tumors and involved in critical processes associated with cancer progression and response to therapy (Monti et al., 2013).
A series of quinoline-based benzenesulfonamides were developed to be potential carbonic anhydrase inhibitors (CAIs).Moreover, the described have been synthesized and investigated for their CA inhibitory action against hCA I, II, IX and XII.In general, parasulphonamide derivatives 52a-c demonstrated the best inhibitory activity against both cancer-related isoforms hCA IX (KIs = 25.8, 5.5 and 18.6 nM, respectively) and hCA XII (KIs = 9.8, 13.2 and 8.7 nM, respectively), beside the excellent hCA IX inhibitory activity exerted by meta-sulphonamide derivative 53 (KI = 8.4 nM) (Shaldam et al., 2021).

Immunomodulating quinolines:
The immunomodulatory activity of targeted anticancer agents originates from the interaction of the drug with cancer cells, as well as from the ability of the drug to interact with, and alter the function of, immune cells.Both these general mechanisms of immunomodulation by targeted anticancer therapy can involve direct or indirect pathways.As an example, targeted anticancer agents can mediate net immunostimulatory effects by promoting the secretion of pro-inflammatory cytokines, or by limiting the release or activity of immunosuppressive factors (Petroni et al., 2021).Roquinimex 54 (linomide®) is the first generation immunomodulatory quinoline-3carboxamide derivative used as anticancer agent.It has an immunostimulant activity as well as it inhibits angiogenesis and reduces the secretion of Tumour Necrosis Factor alpha (TNF alpha).Roquinimex 54 passed phase I, phase II and failed in phase III of clinical trials due to unanticipated serious cardiopulmonary toxicities (Isaacs et al., 2010).

Quinolines as transforming growth factor β inhibitors:
Transforming growth factor β (TGF-β) is a highly pleiotropic cytokine that plays an important role in wound healing, angiogenesis, immunoregulation and cancer.The cells of the immune system produce the TGF-β1 isoform, which exerts powerful anti-inflammatory functions, and is a master regulator of the immune response.The tumor microenvironment contains high concentrations of TGF-β, a crucial immunosuppressive cytokine.TGF-β stimulates immune escape by promoting peripheral immune tolerance to avoid tumoricidal attack.(Prud'homme et al., 2007) (Kharbanda et al., 2021).

(60) (61)
A group of selective 4-aminoquinoline-based compounds was identified as inhibitors of TGFbR1 through structural and rational-based design strategies.This led to the identification of compound 60, which was found to be selective for TGFbR1 with the exception of MAP4K4 in the kinase profiling assay.The compound was then further optimized to remove MAP4K4 activity, since MAP4K4 is vital for proper T-cell function and its inhibition could exacerbate tumor immunosuppression.Optimization efforts led to compound 61 that inhibited TGFbR1 at an IC 50 of 0.79 ± 0.19 nM with 2000-fold selectivity against MAP4K4 (Kharbanda et al., 2021).

Conclusion:
In the end, numerous studies have established the ability of quinoline derivatives to limit cancer cell growth, induce apoptosis, and block angiogenesis, hence inhibiting tumor progression, through considerable research and experimentation.Quinolines' varied modes of action, such as targeting distinct signaling pathways and signaling molecules, make them appealing candidates for further investigation and development as anticancer drugs.However, additional preclinical and clinical trials are required to assess these substances' full therapeutic potential, optimal dose, and potential side effects.Overall, the data reported in this study highlight the importance of quinoline derivatives in cancer research, necessitating more investigation to realize their full potential in the pursuit of better cancer treatments.

.
Pyrotinib (19)is an irreversible dual pan-ErbB receptor tyrosine kinase inhibitor developed for the treatment of HER2-positive advanced solid tumours.(Ayala-Aguilera

et al., 2022).
In 2019, George et al. reported quinoline derivatives quinolinyl based pyrazolines and quinolinyl pyrazolinyl thiazole hybrids which were synthesized and screened for their anti-proliferative activity against three cell lines.Three of tested of potent compounds revealed inhibitory activity at nanomolar level especially compounds 20, 21 and 22 with IC 50(31.80,37.07 and 42.52 nM) compared to Gefitinib (IC 50 = 29.16nM) (George