Inhibition of gene expression has been achieved by targeting the open complex formed during transcription initiation with short, pentameric, modified oligonucleotides.[1] This approach is an alternative to double-stranded (ds) DNA targeting by using triplex-forming oligonucleotides, in which longer probes (> 10 nucleotides) are required for high-affinity binding and specificity.[2] A local opening of the dsDNA by RNA polymerase at the start of transcription is the key to the sequence-selective[a] Dr.

A new set of pyrazolo[3,4-d]pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffolds (4–13) as well as the thioglycoside derivatives (14, 15) were designed, and synthesized as novel CDK2 targeting compounds.

Cyclin-dependent kinase inhibition is considered a promising target for cancer treatment for its crucial role in cell cycle regulation. Pyrazolo pyrimidine derivatives were well established for their antitumor activity via CDK2 inhibition. In this research, new series of pyrazolopyrimidine derivatives ( 4–15 ) was designed and synthesised as novel CDK2 inhibitors. The anti-proliferative activities against MCF-7, HCT-116, and HepG-2 were used to evaluate their anticancer activity as novel CDK2 inhibitors. Most of the compounds showed superior cytotoxic activity against MCF-7 and HCT-116 compared to Sorafenib. Only compounds 8 , 14 , and 15 showed potent activity against HepG-2. The CDK2/cyclin A2 enzyme inhibitory activity was tested for all synthesised compounds. Compound 15 showed the most significant inhibitory activity with IC 50 0.061 ± 0.003 µM. It exerted remarkable alteration in Pre G1 and S phase cell cycle progression and caused apoptosis in HCT cells. In addition, the normal cell line cytotoxicity for compound 15 was assigned revealing low cytotoxic results in normal cells rather than cancer cells. Molecular docking was achieved on the designed compounds and confirmed the two essential hydrogen binding with Leu83 in CDK2 active site. In silico ADMET studies and drug-likeness showed proper pharmacokinetic properties which helped in structure requirements prediction for the observed antitumor activity.

6-Benzyl-5-phenyluracil (4) and 5,6-dibenzyluracil (9) were synthesised from diphenyl acetone (1) and ethyl 3-oxo-4-phenylbutyrate (6), respectively. The uracils were alkylated to afford the 1-alkoxymethyluracils 5, 10 and 11. Furthermore, S-alkylated dihydroalkoxybenzyloxopyrimidine (S-DABO) analogues were prepared by alkylating 5,6-dibenzyl-2-thiouracil (8) on sulfur to yield compounds 12a-f. All compounds were tested for their inhibition of HIV-1 reverse transcriptase, and moderate activity was found for 6-benzyl-1-(ethoxymethyl)-5-phenyluracil (5).

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Background: In recent papers, it was found that 1,3,4-oxadiazole, 1,3,4-thiadiazoleand 1,2,4-triazole pharmacophores are present in several drugs, tiodazosin and nesapidil (antihypertensive), raltegravir (antiretroviral), Furamizole, cefazolin and ceftezole (antibiotics), acetazolamide and methazolamide (carbonic anhydrase inhibitors), sulfamethizole (antibacterial), fluconazole, ravuconazole, voriconazole, itraconazole, posaconazole, and tebuconazole (antifungal). Methods: Thiosemicarbazide was reacted with ethyl p-substituted-phenyl glycinate; namely, ethyl p-tolylglycinate (1), ethyl p-methoxyphenylglycinate (2) or ethyl p-bromophenylglycinate (3), respectively to give compounds 4-6, which then kept with conc. H2SO4 overnight to yield 1,3,4-thiadiazol-2-amine derivatives 7-9. Compounds 10-18 were yielded by reaction of compounds 7-9 with D-sugars namely, D-galactose, D-glucose and/ or D-xylose in ethanol and catalytic amount of acetic acid. Compounds (10-18) were then acetylated with acetic anhydride to form compounds (19-21). Finely compound 7 was reacted with chloroacetyl chloride and/or acetic anhydride to afford compounds 22 and/or 23 respectively. Results: Six compounds were evaluated in vitro for their cytotoxic activity on the HepG-2 and MCF-7 human cancer cell lines. Conclusion: Among the tested compounds, compounds 6 and 13 were found to be the more potent for their cytotoxic activity on the two cancer cell lines.                            Peer Review History: Received: 5 March 2022; Revised: 9 April; Accepted: 1 May, Available online: 15 May 2022 Academic Editor: Dr. Asia Selman Abdullah, Pharmacy institute, University of Basrah, Iraq, asia_abdullah65@yahoo.com UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency.  Received file:                                Reviewer's Comments: Average Peer review marks at initial stage: 6.0/10 Average Peer review marks at publication stage: 7.0/10 Reviewers: Dr. Andrzej Szymański, Poznan University of Technology, Poland, andrzej.szymanski@put.poznan.pl Dr. Bilge Ahsen KARA, Ankara Gazi Mustafa Kemal Hospital, Turkey, ahsndkyc@gmail.com Similar Articles:   CYTOTOXIC ACTIVITIES IN VITRO OF FLOWER EXTRACTS OF THREE SPECIES OF ALOE GROWING IN YEMEN:ALOE RUBROVIOLACEAE, ALOE VERA AND ALOE SABAEA, AGAINST ELEVEN TYPES OF CANCER CELL LINES IN VITRO GENOTOXICITY OF THREE PLANTS FROM ASTERACEAE FAMILY IN HUMAN LYMPHOCYTES CULTURES

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