5657-52-3Relevant academic research and scientific papers
Investigation of the Structure-Activity Relationships of Aza-A-Ring Indenoisoquinoline Topoisomerase i Poisons
Beck, Daniel E.,Reddy, P. V. Narasimha,Lv, Wei,Abdelmalak, Monica,Tender, Gabrielle S.,Lopez, Sophia,Agama, Keli,Marchand, Christophe,Pommier, Yves,Cushman, Mark
, p. 3840 - 3853 (2016/05/24)
Several indenoisoquinolines have shown promise as anticancer agents in clinical trials. Incorporation of a nitrogen atom into the indenoisoquinoline scaffold offers the possibility of favorably modulating ligand-binding site interactions, physicochemical properties, and biological activities. Four series of aza-A-ring indenoisoquinolines were synthesized in which the nitrogen atom was systematically rotated through positions 1, 2, 3, and 4. The resulting compounds were tested to establish the optimal nitrogen position for topoisomerase IB (Top1) enzyme poisoning activity and cytotoxicity to human cancer cells. The 4-aza compounds were the most likely to yield derivatives with high Top1 inhibitory activity. However, the relationship between structure and cytotoxicity was more complicated since the potency was influenced strongly by the side chains on the lactam nitrogen. The most cytotoxic azaindenoisoquinolines 45 and 46 had nitrogen in the 2- or 3-positions and a 3′-dimethylaminopropyl side chain, and they had MGM GI50 values that were slightly better than the corresponding indenoisoquinoline 64.
Discovery of potent indenoisoquinoline topoisomerase i poisons lacking the 3-nitro toxicophore
Beck, Daniel E.,Abdelmalak, Monica,Lv, Wei,Reddy, P. V. Narasimha,Tender, Gabrielle S.,O'Neill, Elizaveta,Agama, Keli,Marchand, Christophe,Pommier, Yves,Cushman, Mark
, p. 3997 - 4015 (2015/05/27)
3-Nitroindenoisoquinoline human topoisomerase IB (Top1) poisons have potent antiproliferative effects on cancer cells. The undesirable nitro toxicophore could hypothetically be replaced by other functional groups that would retain the desired biological activities and minimize potential safety risks. Eleven series of indenoisoquinolines bearing 3-nitro bioisosteres were synthesized. The molecules were evaluated in the Top1-mediated DNA cleavage assay and in the National Cancer Institute's 60 cell line cytotoxicity assay. The data reveal that fluorine and chlorine may substitute for the 3-nitro group with minimal loss of Top1 poisoning activity. The new information gained from these efforts can be used to design novel indenoisoquinolines with improved safety.
Diastereoselective routes toendo andexo ethyl 1-azabicyclo[2.2.1] hept-3-YL carboxylates
Orlek, Barry S.,Wadsworth, Harry,Wyman, Paul,Hadley, Michael S.
, p. 1241 - 1244 (2007/12/18)
Diastereoselective routes to endo and exo ethyl 1-azabicyclo[2.2.1]hept-3-yl carboxylates (1) and (2) based on the hydrogen bromide cleavage of the isomeric [4.3.0] bicyclic cis fused lactones (3) and (4) are described.
Comparison of Azabicyclic Esters and Oxadiazoles as Ligands for the Muscarinic Receptor
Orlek, Barry S.,Blaney, Frank E.,Brown, Frank,Clark, Michael S. G.,Hadley, Michael S.,et al.
, p. 2726 - 2735 (2007/10/02)
The link between the cognitive deficit associated with Alzheimer type dementia and the loss of cholinergic function in the disease provides a basis for examining muscarinic agonists as potential therapeutic agents.This paper describes the design and synthesis of novel azabicyclic methyl esters as ligands for the muscarinic receptor.Replacement of the methyl ester by a 3-methyl-1,2,4-oxadiazole ring produces potent metabolically more stable muscarinic agonists capable of penetrating the central nervous system.These compounds generally show improved affinity relativeto the corresponding methyl esters. 3-Methyl-1,2,4-oxadiazole 7b has an affinity 4 times that of acetylcholine.Receptor affinity is discussed in relation to the size and geometry of the azabicyclic ring and the electronic properties of the heteroaromatic ring.
Aza analogues of protoberberine and phtalideisoquinoline alkaloids
Jahangir,MacLean, David B.,Holland, Herbert L.
, p. 1031 - 1035 (2007/10/02)
Anions derived from furopyridin-3(1H)-one, by treatment with lithium diisopropylamide, react with substituted, 3,4-dihydroisoquinolines and 2-methyl-3,4-dihydroisoquinolinium salts yielding nitrogen analogues of protoberberine and phtalideisoquinoline alkaloids, respectively.
Radiation-induced Alkylation, Hydroxyalkylation, and Reduction of Pyridinecarboxamides in Acidic Alcoholic Solutions
Sugimori, Akira,Nishijima, Masayuki,Itoh, Hiroshi
, p. 3055 - 3056 (2007/10/02)
The γ-irradiation of pyridinecarboxamides in acidic methanol or ethanol brings about substitution of the ring hydrogen by alkyl or hydroxyalkyl groups derived from the solvent alcohols in relatively high G-values.In 2-propanol, little alkylation and hydroxyalkylation occur and reduction of CONH2 to CH2OH occurs in low G-values.
