- Optimization of 4,6-Disubstituted Pyrido[3,2-d]pyrimidines as Dual MNK/PIM Inhibitors to Inhibit Leukemia Cell Growth
-
Mitogen-activated protein kinase-interacting kinases (MNKs) and provirus integration in maloney murine leukemia virus kinases (PIMs) are downstream enzymes of cell proliferation signaling pathways associated with the resistance of tyrosine kinase inhibitors. MNKs and PIMs have complementary effects to regulate cap-dependent translation of oncoproteins. Dual inhibitors of MNKs and PIMs have not been developed. We developed a novel 4,6-disubstituted pyrido[3,2-d]pyrimidine compound 21o with selective inhibition of MNKs and PIMs. The IC50’s of 21o to inhibit MNK1 and MNK2 are 1 and 7 nM and those to inhibit PIM1, PIM2, and PIM3 are 43, 232, and 774 nM, respectively. 21o inhibits the growth of myeloid leukemia K562 and MOLM-13 cells with GI50’s of 2.1 and 1.2 μM, respectively. 21o decreases the levels ofp-eIF4E andp-4EBP1, the downstream products of MNKs and PIMs, as well as cap-dependent proteins c-myc, cyclin D1, and Mcl-1. 21o inhibits the growth of MOLM-13 cell xenografts without causing evident toxicity. 21o represents an innovative dual MNK/PIM inhibitor with a good pharmacokinetic profile.
- Han, Yu,Zhang, Huimin,Wang, Shuxiang,Li, Bo,Xing, Kun,Shi, Yuntao,Cao, Hongxue,Zhang, Jian,Tong, Tong,Zang, Jie,Guan, Lihong,Gao, Xiaoxiao,Wang, Yuetong,Liu, Dan,Huang, Min,Jing, Yongkui,Zhao, Linxiang
-
p. 13719 - 13735
(2021/10/01)
-
- 4, 6-disubstituted pyridine [3, 2-d] pyrimidine compound as well as preparation and application thereof
-
The invention belongs to the technical field of medicines. The invention relates to the field of pharmaceutical chemistry, in particular to a 4, 6-disubstituted pyridine [3, 2-d] pyrimidine compound and pharmaceutically acceptable salt thereof, a preparation method of the compound, a pharmaceutical composition taking the compound as an active ingredient, and application of the compound in preparation of an MNK inhibitor and drugs for treating and/or preventing various cancers and/or metabolic diseases. The present invention relates to compounds represented by formulas I, II, III or IV, and pharmaceutically acceptable salts, hydrates, solvates and metabolites thereof, wherein the variables are described in the claims and the description.
- -
-
Paragraph 0100-0103
(2020/04/02)
-
- NITRATION
-
The present invention relates to a process for preparing a nitrated compound, comprising the step of reacting a compound (A) comprising at least one substituted or unsubstituted aromatic or heteroaromatic ring, wherein said heteroaromatic ring comprises at least one heteroatom selected from the group consisting of oxygen, sulfur, phosphor, selenium and nitrogen, with a compound of formula (I) wherein Y is selected from the group consisting of hydrogen and nitro.
- -
-
Page/Page column 36; 37; 49; 39; 53
(2020/05/28)
-
- N-Nitroheterocycles: Bench-Stable Organic Reagents for Catalytic Ipso-Nitration of Aryl- And Heteroarylboronic Acids
-
Photocatalytic and metal-free protocols to access various aromatic and heteroaromatic nitro compounds through ipso-nitration of readily available boronic acid derivatives were developed using non-metal-based, bench-stable, and recyclable nitrating reagents. These methods are operationally simple, mild, regioselective, and possess excellent functional group compatibility, delivering desired products in up to 99% yield.
- Budinská, Alena,Katayev, Dmitry,Passera, Alessandro,Zhang, Kun
-
supporting information
(2020/03/30)
-
- Development of substituted pyrido[3,2-d]pyrimidines as potent and selective dihydrofolate reductase inhibitors for pneumocystis pneumonia infection
-
Pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii (pj) can lead to serious health consequences in patients with an immunocompromised system. Trimethoprim (TMP), used as first-line therapy in combination with sulfamethoxazole, is a selective but only moderately potent pj dihydrofolate reductase (pjDHFR) inhibitor, whereas non-clinical pjDHFR inhibitors, such as, piritrexim and trimetrexate are potent but non-selective pjDHFR inhibitors. To meet the clinical needs for a potent and selective pjDHFR inhibitor for PCP treatment, fourteen 6-substituted pyrido[3,2-d]pyrimidines were developed. Comparison of the amino acid residues in the active site of pjDHFR and human DHFR (hDHFR) revealed prominent amino acid differences which could be exploited to structurally design potent and selective pjDHFR inhibitors. Molecular modeling followed by enzyme assays of the compounds revealed 15 as the best compound of the series with an IC50 of 80 nM and 28-fold selectivity for inhibiting pjDHFR over hDHFR. Compound 15 serves as the lead analog for further structural variations to afford more potent and selective pjDHFR inhibitors.
- Shah, Khushbu,Queener, Sherry,Cody, Vivian,Pace, Jim,Gangjee, Aleem
-
supporting information
p. 1874 - 1880
(2019/06/08)
-
- Preparation method of 2,6-dichloro-3-nitropyridine
-
The invention relates to a 2,6-Dichloro-3-Preparation method of nitropyridine. The method uses 2-Nitroacetate and 2-Halogenated acrylates are catalyzed by organic bases for 1,4-Addition reaction followed by cyclization reaction with ammonia to obtain 2,6-Dihydroxy-3-Nitropyridine is then reacted with a chlorinating reagent to produce 2,6-Dichloro-3-Nitropyridine. The invention does not use concentrated sulfuric acid and nitric acid, the used raw materials are cheap and easily available, the operation is simple and convenient, the conditions are mild, the amount of waste water is small, the invention is safe and environment-friendly and the cost is low.
- -
-
Paragraph 0040-0045
(2019/10/01)
-
- MONOCYCLIC, THIENO, PYRIDO, AND PYRROLO PYRIMIDINE COMPOUNDS AND METHODS OF USE AND MANUFACTURE OF THE SAME
-
The present invention provides monocyclic, thieno, pyrido and pyrrolo pyrimidine compounds. Pharmaceutical compositions comprising one or more of these compounds and optionally comprising a pharmaceutically acceptable salt or hydrate of one or more of the compounds are provided. Preferably, these pharmaceutical compositions further comprise at least one pharmaceutically acceptable carrier. Methods of treating a patient having cancer are provided wherein a therapeutically effective amount of one or more of these compounds or pharmaceutical compositions are administered to the patient.
- -
-
Page/Page column 33-34
(2017/03/21)
-
- A 5 (4H)-pyridone combines furazane oxide synthesis method
-
The invention discloses a synthesis method of 4H-pyridofuroxan-5-one (III, also known as 4H, 5H-(1, 2, 5) oxadiazole (3, 4-b) pyridin-5-one-1-oxide). The synthesis method comprises the following steps (see the following reaction formula): enabling 2-amino-3-nitro-6-chloropyridine (I) to react with potassium (or sodium and the like) fluoride in a water-containing alcohol type solution, or enabling I to react with a nitrite in acetone to prepare 2-amino-3-nitro-6-hydroxypyridine (II); then performing oxidation and condensation reaction under alkaline conditions to prepare III. The synthesis process disclosed by the invention is simple and convenient to operate, and suitable for relatively large-scale production of III; a new way is provided for preparing anti-virus and anti-tumor compounds with the effect of releasing nitric oxide (NO).
- -
-
Paragraph 0032-0033
(2017/04/11)
-
- Oxidation potentials of N-modified derivatives of the analgesic flupirtine linked to potassium KV7 channel opening activity but not hepatocyte toxicity
-
Openers of neuronal voltage-gated potassium channels (KV) are of interest as therapeutic agents for treating pain (flupirtine) and epilepsy (retigabine). In an effort to better understand the mechanisms of action and toxicity of flupirtine, we synthesized nine novel analogues with varying redox behavior. Flupirtine can be oxidatively metabolized into azaquinone di-imines; thus, the oxidation potentials of flupirtine and its analogues were measured by cyclic voltammetry. KV7.2/3 (KCNQ2/3) opening activity was determined by an established assay with HEK293 cells overexpressing these channels. A link was found between the oxidation potentials of the compounds and their EC50 values for potassium channel opening activity. On the other hand, no correlation was observed between oxidation potentials and cytotoxicity in cultures of transgenic mouse hepatocytes (TAMH). These results support the idea that oxidative metabolites of flupirtine contribute to the mechanism of action, similar to what was recently proposed for acetaminophen (paracetamol), but not to hepatotoxicity.
- Lemmerhirt, Christian J.,Rombach, Mirko,Bodtke, Anja,Bednarski, Patrick J.,Link, Andreas
-
p. 368 - 379
(2015/02/05)
-
- INHIBITORS OF DNA GYRASE FOR THE TREATMENT OF BACTERIAL INFECTIONS
-
The present invention relates to compounds which specifically inhibit bacterial DNA Gyrase and can be used for the treatment of respiratory tract infections.
- -
-
Page/Page column 47
(2014/05/07)
-
- Process for producing 2,3-diamino-6-methoxypyridine
-
The present invention relates to a novel process for producing 2,3-diamino-6-methxoypyridine. The process comprises neutralizing 2,3-diamino-6-methoxy pyridine dihydrochloride, which, in turn, is prepared by the reduction of 2-amino-6-methoxy-3-nitropyridine. The 2-amino-6-methoxy-3-nitropyridine is further prepared by methoxylation of 2-amino-6-chloro-3-nitropyridine by sodium methoxide in methanol.
- -
-
Page/Page column 2
(2008/06/13)
-
- 6-Substituted 2,4-diaminopyrido[3,2-d]pyrimidine analogues of piritrexim as inhibitors of dihydrofolate reductase from rat liver, Pneumocystis carinii, and Toxoplasma gondii and as antitumor agents
-
The synthesis and biological activity are reported for 21 6-substituted 2,4-diaminopyrido[3,2-d]pyrimidine analogues (4-24) of piritrexim (PTX) as inhibitors of dihydrofolate reductase (DHFR) and as antitumor agents. Recombinant DHFR from Pneumocystis carinii (pc) and native DHFR from Toxoplasma gondii (tg) were the target enzymes tested; these organisms are responsible for fatal opportunistic infections in AIDS patients. Rat liver (rl) DHFR served as the mammalian reference enzyme to determine selectivity for the pathogenic DHFR. The synthesis of S9-bridged compounds 4-6 was achieved by aryl displacement of 2,4-diamino-6-chloropyrido[3,2-d]pyrimidine (27) with thiol nucleophiles. Oxidation of 4-6 with hydrogen peroxide in glacial acetic acid afforded the corresponding sulfone analogues 7-9. The N9- bridged compounds 10-24 were synthesized from their precursor 3-amino-6- (arylamino)-2-pyridinecarbonitriles via a thermal cyclization with chloroformamidine hydrochloride. Unlike the S9-bridged compounds, the arylamino side chains of the N9-bridged analogues were introduced prior to the formation of the 2,4-diaminopyrido[3,2-d]pyrimidine nucleus. A reversed two-atom-bridged analogue (25) was also synthesized using a synthetic strategy similar to that utilized for compounds 10-24. The IC50 values of these compounds against pcDHFR ranged from 0.0023 x 10-6 M for 2,4-diamino- 6-(N-methyl-3',4'-dimethoxyanilino)pyrido[3,2-d]pyrimidine (21), which was the most potent, to 90.4 x 10-6 M for 2,4-diamino-6-(4'-methoxyanilino)- pyrido[3,2-d]pyrimidine (12), which was the least potent. The three S9- bridged compounds tested were more potent than the corresponding sulfone- bridged compounds for all three DHFRs. N9-Methylation increased the potency by as much as 17 000-fold (compounds 15 and 21). None of the analogues were selective for pcDHFR. Against tgDHFR the most potent analogue was again 21 with an IC50 value of 0.00088 x 10-6 M and the least potent was 12 with an IC50 of 2.8 x 10-6 M. N9-Methylation afforded an increase in potency of up to 770-fold (compound 15 NH vs 21 N-CH3) compared to the corresponding N9-H analogue. In contrast to pcDHFR, several analogues had a greater selectivity ratio for tgDHFR compared to trimetrexate (TMQ) or PTX, most notably 2,4-diamino-6-[(3',4'-dimethoxyphenyl)thio]pyrido[3,2-d]pyrimidine (4), 2,4-diamino-6-[(2'-methoxyphenyl)sulfonyl]pyrido[3,2-d]pyrimidine (7), and 2,4-diamino-6-(2',5'-dimethoxyanilino)pyrido[3,2-d]pyrimidine (14) which combined relatively high potency at 10-7-10-8 M along with selectivity ratios of 3.97, 6.67, and 4.93, respectively. Several analogues synthesized had better selectivity ratios than TMQ or PTX for both pcDHFR and tgDHFR, and the potencies of the N9-methylated compounds were comparable to or greater than that of TMQ or PTX. Selected compounds were evaluated as inhibitors of the growth of a variety of tumor cells in culture. The N9-CH3 analogues were, in general, highly potent with GI50 values in the nanomolar range. The N9-H and S9 analogues were less potent with GI50 values in the millimolar to micromolar range.
- Gangjee, Aleem,Zhu, Yuanming,Queener, Sherry F.
-
p. 4533 - 4541
(2007/10/03)
-
- Aprotic Nitration (NO2+BF4-) of 2-Halo- and 2,6-Dihalopyridines and Transfer-Nitration Chemistry of Their N-Nitropyridinium Cations
-
NO2+BF4- nitration of 2,6-dibromo-1 and 2,6-dichloropyridine 2 in CH3CN results in predominant C-nitration, whereas in CH2Cl2, N-nitration is predominant.With 2,6-difluoropyridine 3 only C-nitration was observed.Dehalogenation of the C-nitrated 1 and 2 affords 3-nitropyridine (3-NP) in moderate but greatly improved yields over conventional protic nitration of pyridine.Despite favorable presence of steric inhibition to resonance and the I-effect of halogens, N-nitrated pyridinium salts 1b and 2b do not transfer-nitrate to aromatics even under forcing conditions.The lack of transfer-nitration reactivity is not due to in situ rearrangement of the nitro onium to nitrito oniums ions.A mechanism involving neighboring group participation by the 2,6-halogens is proposed.The monohalo-N-nitropyridinium cations transfer-nitrate toluene and benzene.Transfer nitration selectivity of the 2-bromo-N-nitro- and 2-chloro-N-nitropyridinium cations are comparable (KT/KB = 41-44), but the 2-fluoro-N-nitro cation is much less selective (more reactive) (KT/KB = 15.4), indicative of a stronger -I effect, weakening the N+-N+ bond.
- Duffy, Joseph L.,Laali, Kenneth Khosrow
-
p. 3006 - 3009
(2007/10/02)
-
- REACTIVITIES OF HETEROCYCLIC COMPOUNDS IN NITRATION. 7. EXPERIMENTAL AND THEORETICAL STUDY OF THE REACTIVITIES OF PYRIDINES
-
The relationship between the rates of nitration of pyridines and the calculated indexes of aromatic electrophilic substitution was investigated.The possibility of the use of two-center components of the location energies for the theoretical description of the reactivities of pyridines in nitration is demonstrated.The rates of nitration of a number of previously uninvestigated pyridines are predicted.
- Sharnin, G. P.,Saifullin, I. Sh.,Falyakhov, I. F.,Khairutdinov, F. G.,Bol'shakova, T. G.,Zverev, V. V.
-
p. 514 - 517
(2007/10/02)
-
