Pyrido[2,3-d]pyrimidin-7-ones as Specific Inhibitors of Cyclin-Dependent Kinase 4

Abstract

Inhibition of the cell cycle kinase, cyclin-dependent kinase-4 (Cdk4), is expected to provide an effective method for the treatment of proliferative diseases such as cancer. The pyrido[2,3-d]pyrimidin-7-one template has been identified previously as a privileged structure for the inhibition of ATP-dependent kinases, and good potency against Cdks has been reported for representative examples. Obtaining selectivity for individual Cdk enzymes, particularly Cdk4, has been challenging. Here, we report that the introduction of a methyl substituent at the C-5 position of the pyrido[2,3-d]pyrimidin-7-one template is sufficient to confer excellent selectivity for Cdk4 vs other Cdks and representative tyrosine kinases. Further optimization led to the identification of highly potent and selective inhibitors of Cdk4 that exhibit potent antiproliferative activity against human tumor cells in vitro. The most selective Cdk4 inhibitors were evaluated for antitumor activity against MDA-MB-435 human breast carcinoma xenografts in mice.

Green and Efficient Synthesis of Some Pyrido[2,3-D]Pyrimidin-4(3h)-One Derivatives Via Iodine Catalyst in Aqueous Media and Evaluation the Synthesized Compounds as Anticancer

“…2-propyl-4H-pyrido [2,3-d] [1,3] oxazin-4-one (2) has been synthesized from the interaction of butyroyl chloride with 2-aminonicotinic acid in pyridine to give 2-propyl-4H-pyrido [2,3-d] [1,3]oxazin-4-one (2). The structure of compound 2 was inferred from its IR spectra (cm -1 ) which exhibits strong absorption bands at 1614, 1764 (cm -1 ) due to υ max .of C=N and C=O of pyridoxazinone and lack of any band for NH and / or OH.…”

“…The structure of compound 2 was inferred from its IR spectra (cm -1 ) which exhibits strong absorption bands at 1614, 1764 (cm -1 ) due to υ max .of C=N and C=O of pyridoxazinone and lack of any band for NH and / or OH. The starting compound 3a was prepared via reacting pyridooxazinone (2) with hydrazine hydrate in ethanol in water path, the formation of compound 3a was confirmed by 1 HNMR that showed singlet signal at ᵟ 9.8ppm and from its IR spectrum which exhibits strong absorption bands at 1614 and 1670 (cm -1 ) due to υ max . of C=N, C=O and lack of any band for of C=O of pyridoxazinone, also compound 2 was reacted with ammonium acetate in an oil bath to form 2-propylpyrido [2,3-d]pyrimidin-4(3H)-one (3b).…”

“…Mass spectrometry were recorded were recorded Shomadzu, GC -MS (QP -1000EX 2-propyl-4H-pyrido [2,3-d] [1,3]oxazin-4-one (2) A stirred solution of 2-aminonicotinic acid 13.8g (0.1 mol) in dry pyridine (150 ml) was treated drop wise with nbutyroyl chloride 10.5g (0.11 mol) during 10 min. the mixture was stirred at room temperature (3hours) and poured into a mixture of ice and hydrochloric acid gave crude 2-propyl-4H-pyrido [2,3-d] [1,3]oxazin-4-one The precipitated solid was filtered off , washed with cold water and recrystallization from petroleum ether 40 -60 oC, giving 2-propyl-4H-pyrido [2,3-d] [1,3]oxazin-4-one (2) as a colorless crystals melting point(63 oC) (2) Compound (2) (1.89 g-10mmol) and 5 ml hydrazine hydrate were heated in water bath for 1/2 hour and then added 50ml ethanol the mixture was refluxed, The completion of the reaction was monitored by TLC using chloroform: methanol (8:2) as eluent and the obtained solid was filtered off and recrystalization from petroleum ether 60-80 o C to give 3-amino-2-propylpyrido [2,3-d] N 3 O : C, 63.45; H, 5.79; N, 22.20 method B-2-propyl-4H-pyrido [2,3-d] [1,3]oxazin-4-one (2) (1mmol) in formamide (20 ml) was refluxed for 3 hours, the reaction mixture was cooled and poured in cold water. The obtained solid was filtered off and recrystalized from the proper solvent IR(KBr) cm A solution of compound (2) (10mmol) and hydroxylamine hydrochloride in boiling ethanol (25 ml) was refluxed for 3 hours.…”

“…The IC50 of the synthesized compounds compared to the reference drug are shown in Table 4. From the results in Table (3), it was found that the best results were obtained by compounds pyrido [2,3-d] [1,3]oxazin (2), 3-amino derivative 3a, 3b and hydroxy derivative 3c. Regarding the chloro 4c and hydroxyl substituted 4i-k give moderate activity.…”

“…The pyrido [2,3-d]pyrimidine nucleus represents in many biologically active compounds which includes antitumour [1][2][3][4][5][6][7], antibacterial [8], anticonvulsant [9], antipyretic [10], analgesic [11], and CNS depressant activity [12]. Specifically pyrido [2,3-d]pyrimidines known to inhibit Pneumocystis carinii(pc), Toxoplasma gondii(tg) of tumor cell lines in culture [13] and the activity is attributed to inhibition of dihydrofolate reductase (DHFR) [14,15].…”