Molecular Modelling and Cytotoxicity of Substituted Anthraquinones as Inhibitors of Human Telomerase

Chen

CHEMICAL & PHARMACEUTICAL BULLETIN

et al. 2007

Most human somatic cells divide 50-60 times before senescence occurs. These cells invariably enter a state of irreversibly arrested growth. This process, termed replicative senescence, is thought to be a tumor-suppressive mechanism and an underlying cause of aging.1) The molecular mechanism underlying cellular senescence has been characterized. It is well accepted that telomeres play a major role in the process. Telomeres are the physical ends of linear eukaryotic chromosomes. They consist of hundreds to thousands of tandem repeats of the sequence TTAGGG, that are essential for stabilizing chromosomes.2) Because conventional DNA polymerase cannot replicate the very end of chromosomes, telomere length is shortened upon each DNA replication. Telomerase is the enzyme activity that elongates short telomeres. Because telomerase activity is low or not detectable in most normal human somatic cells, telomeric DNA is progressively shortened with each cell division. The shortened telomeres then signal cells to enter senescence through a DNA damage signaling pathway. Telomere length is considered as a biological clock that is capable of determining the proliferative capacity of most human somatic cells. 3,4)While telomerase is not detected or is low in most of the normal human cells, it is detected in ca. 85-90% of the immortalized or tumor cells. In humans, telomerase activity is tightly regulated by expression of the human telomerase reverse transcriptase (hTERT) gene, which appears to be the key regulator for telomerase activity. Inhibition or activation of the hTERT expression could profoundly affect the proliferative capacity of normal cells and cancers.5-7) Because telomerase is required for the sustained proliferation of most immortal cells, including cancer cells, it has become the focus of much attention as a novel and potentially highlyspecific target for the development of new anticancer chemotherapeutics. In this respect, antisense oligonucleotides or small molecular inhibitors have been identified as inhibitors to telomerase. 8) Several of them effectively inhibit telomerase in vitro and limit the proliferation of cancer cells in vivo.9) However, because a lag period is required for telomeres to be shortened to critical short length, the clinical applicability of telomerase inhibitor was questioned. For example, it takes ca. 20 additional cell divisions for telomeres of HeLa cells to be shortened to critical length.8) It is not realistic for telomerase inhibitor to be used in treating cancers. Thus, it was proposed that telomerase inhibitors should work with other chemotherapeutic agents for treating cancers.10)The use of cytotoxic agents to kill cancer cells and telomerase inhibitor to limit the proliferative potential of residual cancer cells should be a better approach in cancer chemotherapy. Interestingly, guanine-quadruplex (G-quadruplex) stabilizers such as 2,6-pyridine-dicarboxamide derivatives and 3,6,9-trisubstituted acridine compounds caused accelerated senescence in cancer cells. Molecules able to s...

Section: Biological Activity and Discussionmentioning

confidence: 99%

Synthesis and Human Telomerase Inhibition of a Series of Regioisomeric Disubstituted Amidoanthraquinones

Chen

CHEMICAL & PHARMACEUTICAL BULLETIN

et al. 2007

CHEMICAL & PHARMACEUTICAL BULLETIN

“…11,12,21) The synthesized compounds compete with the natural substrate to its binding domain and this resulted in the inhibition of the enzyme reaction. The calculations based on this theory relayed initially on calculating the free energy of binding of designed and docked inhibitors in to the binding domain of the methionine synthase and the free energy of the receptor and the ligand individually (Eq.…”

Section: Theory-calculationmentioning

confidence: 99%

Molecular Modeling Studies and Synthesis of Novel Methyl 2-(2-(4-Oxo-3-aryl-3,4-dihydroquinazolin-2-ylthio)acetamido)alkanoates with Potential Anti-cancer Activity as Inhibitors for Methionine Synthase

Elfekki

Hassan

Elshihawy

et al. 2014

Cobalamin-dependant cytosolic enzyme methionine synthase (MetS) catalyses the transfer of a methyl group from the methyltetrahydrofolate (MTHF) to homocysteine (Hcy) to produce methionine and tetrahydrofolate (THF). MetS is over-expressed in the cytosol of certain breast and prostate tumour cells. Methionine used as a source of one carbon atom for the building of the DNA of the tumour cells, structural protein and enzymes. In this study, we designed, synthesized and evaluated the cytotoxic activity of a series of substituted methyl 2-(2-(4-oxo-3-aryl-3,4-dihydroquinazolin-2-ylthio)acetamido)acetate and dipeptide that mimic the substructure of MTHF. Key words cobalamin: methionine; methionine synthase; quinozaline; thioamide; chemoselective reaction Methionine synthase (MetS) is one of the folic acid cycle enzymes that catalyses the transfer of a methyl group from 5-methyltetrahydrofolate to homocysteine to produce methionine and tetrahydrofolate. The catalysis occurred via the coenzyme cobalamin cofactor (CH 3 -Cb).1) This enzyme has been linked to the pathogenesis of anemias, neurodegenerative disorders and cancer.2) Using mammalian methionine synthase, X-ray studies show that it is constructed of 1227 amino acid residues and has a molecular mass of 136 kDa. 3)Cobalamin-dependent methionine synthase is made up of four modules 5-methyltetrahydrofolate and homocysteine binding regions from the C-terminal of the protein and cobalamin and the S-adenosylmethionine binding regions from N-terminal. 3)Methionine is an essential amino acid necessary for normal growth. Methionine is used as a methyl group donor, providing one carbon units for DNA synthesis.4) Methionine dependence is defined as the inability of cancer cells to grow in a methionine depleted medium even when replaced with the immediate precursor, homocysteine.5) Normal cells remain unaffected by methionine restrictions if supplemented with homocysteine, as they are able to synthesize methionine via methylation of homocysteine in sufficient quantities. Most metastatic tumours, such as those originating in prostate, lung and gastrointestinal tract, respond poorly to conventional chemotherapy. Novel treatment strategies for advanced cancer are therefore needed. Dietary restriction of the essential amino acid methionine offers promise as such a strategy, either alone or in combination with chemotherapy or other treatments. 6)Although there are many approaches for developing inhibitors for folic acid enzymes system collectively named antifolates.There are a limited number of reports concerning the inhibition of MetS. A series of inhibitors of substituted 2,4-diaminopyrimidine derivatives that could bind the substrate-binding pocket of dihydrofolate reductase was synthesized.7) 6-Substituted pyrrolo-and thieno[2,3-d]pyrimidine derivatives were identified as antifolates with selective membrane transport by proton-coupled folate transporter (PCFT) and folate receptors (FRs) over reduced folate carrier (RFC).8) A series of pyrido [2,3-d] pyrimidines was successful...

“…All of these identified compounds have planar aromatic rings. Molecular modeling studies have indicated that these planar structures bind to the G-quadruplexes through a series of interactions to the planar and loop structures of G-quadruplexes [28,38,39] . These interactions stabilize the structure of G-quadruplexes and increase the melting temperature upon binding.…”

Section: Inhibition Of Telomerase Activitymentioning

confidence: 99%

Telomere and telomerase as targets for anti-cancer and regeneration therapies

Hsu¹,

Lin²

2005

Acta Pharmacol Sin

Telomerase is a ribonucleoprotein that directs the synthesis of telomeric sequence. It is detected in majority of malignant tumors, but not in most normal somatic cells. Because telomerase plays a critical role in cell immortality and tumor formation, it has been one of the targets for anti-cancer and regeneration drug development. In this review, we will discuss therapeutic approaches based mainly on small molecules that have been developed to inhibit telomerase activity, modulate telomerase expression, and telomerase directed gene therapy.