Study on the cyclization of 6-arylethynylpyrimidine-5-carbaldehydes with tert-butylamine: microwave versus thermal preparation of pyrido[4,3-d]pyrimidines

Thermal and microwave initiated cyclization of 2,4-disubstituted 6-arylethynylpyrimidine-5-carbalde hydes with tert-butylamine has been studied. A novel high-yielding preparation of 2,4-disubstituted 7- arylpyrido[4,3-d]pyrimidines has been developed. The intermediate compounds were isolated and possible mechanism of the reactions is discussed.info:eu-repo/semantics/publishedVersio

The first example of the Fischer–Hepp type rearrangement in pyrimidines

A N-nitroso moiety can be used for the activation of chloropyrimidines toward a nucleophilic substitution reaction with amines. The subsequent treatment of the obtained products with aq H2SO4 can lead to either N-denitrosation to obtain 4,6-pyrimidinediamines or to a Fischer–Hepp type rearrangement to obtain 5-nitroso-4,6-pyrimidinediamines. It was found that the outcome of the reaction strongly depends on the structure of the pyrimidines. Activation of the pyrimidine ring by three groups with a positive mesomeric effect is crucial for the intramolecular nitroso group migration

A Unique Cascade Reaction between 3‑Arylprop-2-inylcarboxylates and Benzaldehydes Leading to the Formation of Morita–Baylis–Hillman Adducts

During an alkyne-carbonyl metathesis reaction between electron-rich 3-arylprop-2-inylcarboxylates and electron-poor benzaldehydes, a smooth migration of carboxylate groups takes place. This unique cascade reaction allows the formation of Morita–Baylis–Hillman (MBH) adducts unavailable via a traditional MBH reaction

CKT0353, a novel microtubule targeting agent, overcomes paclitaxel induced resistance in cancer cells.

Microtubule targeting agents (MTAs) are extensively used in cancer treatment and many have achieved substantial clinical success. In recent years, targeting microtubules to inhibit cell division has become a widespread pharmaceutical approach for treatment of various cancer types. Nevertheless, the development of multidrug resistance (MDR) in cancer remains a major obstacle for successful application of these agents. Herein, we provided the evidence that CKT0353, α-branched α,β-unsaturated ketone, possesses the capacity to successfully evade the MDR phenotype as an MTA. CKT0353 induced G2/M phase arrest, delayed cell division via spindle assembly checkpoint activation, disrupted the mitotic spindle formation and depolymerized microtubules in human breast, cervix, and colorectal carcinoma cells. Molecular docking analysis revealed that CKT0353 binds at the nocodazole binding domain of β-tubulin. Furthermore, CKT0353 triggered apoptosis via caspase-dependent mechanism. In addition, P-glycoprotein overexpressing colorectal carcinoma cells showed higher sensitivity to this agent when compared to their sensitive counterpart, demonstrating the ability of CKT0353 to overcome this classic MDR mechanism involved in resistance to various MTAs. Taken together, these findings suggest that CKT0353 is an excellent candidate for further optimization as a therapeutic agent against tumors with MDR phenotype.This is a post-peer-review, pre-copyedit version of an article published in Investigational New Drugs. The final authenticated version is available online at: [http://dx.doi.org/10.1007/s10637-019-00803-6