44768-60-7Relevant articles and documents
THIOL-ENE CLICK CHEMISTRY FOR DRUG CONJUGATES
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Paragraph 0284, (2014/01/07)
The present invention relates to linker molecules that readily conjugate cellular recognition ligand at one end and drug payload at the other, and are useful in treating or preventing cancer, an autoimmune disease, an inflammatory condition, a central nervous system disorder or an infection. The linker inker molecules of the invention are represented by Formula I, II and III; Linker-Drug compounds represented by Formula IV, V and VI; and Ligand-Linker-Drug conjugates represented by Formula VII, VIII and IX:
Intensely potent doxorubicin analogues: Structure-activity relationship
Farquhar, David,Cherif, Abdallah,Bakina, Elena,Arly Nelson
, p. 965 - 972 (2007/10/03)
N-(5,5-Diacetoxypent-1-yl)doxorubicin (1b) is an intensely cytotoxic doxorubicin analogue that retains full potency against tumor cells that express elevated levels of P-glycoprotein and are resistant to doxorubicin. 1b was designed to be hydrolyzed in the presence of carboxylate esterases to N-(5-oxypent-1-yl)doxorubicin, an aldehyde capable of existing in equilibrium with a cyclic carbinolamine. To investigate the structural determinants of potency for 1b, we have prepared a series of chemically related compounds in which various ω-[bis(acetoxy)]alkyl or ω-[bis(acetoxy)]alkoxyalkyl groups are substituted at the 3'-amino position of the daunosamine sugar. These groups were selected to assess the effect of chain length, oxygen substitution, and carbinolamine ring size on analogue potency. The compounds were evaluated for their ability to inhibit the in vitro growth of the following cell lines: (a) Chinese hamster ovary (CHO) cells, (b) a CHO cell mutant 100-fold resistant to doxorubicin that expresses elevated levels of P- glycoprotein, (c) a murine ductal cell pancreatic adenocarcinoma (Panc 02), and (d) a murine mammary carcinoma (CA 755). The most potent members of the series were those that could form a straight chain aldehyde intermediate after esterase-mediated hydrolysis of the ω-bis(acetoxy) groups and give rise to 5- or 6-membered ring carbinolamines. Analogues capable of forming 7- , 8-, or 9-membered carbinolamines were markedly less active. The N-methyl derivative of 1b, which cannot give rise to a cyclic carbinolamine, was 2 orders of magnitude less potent than 1b. A branched chain analogue, 1f, which contained a tertiary carbon atom adjacent to the ω-bis(acetoxy) groups, was also substantially less active than its nonbranched counterpart, 1a. These findings suggest that the chain length of the 3'-amino substituents and the ability of the derived aldehydes to form 5- or 6-membered carbinolamines are critical determinants of biologic potency.
Intramolecular Cycloaddition of Nitrones
Aurich, Hans Guenter,Boutahar, Mostafa,Koester, Heiner,Moebus, Klaus-Dieter,Ruiz, Luis
, p. 1999 - 2014 (2007/10/02)
Nitrones 9 and 10, formed by treatment of the corresponding aldehydes with N-substituted hydroxylamines, are converted into the cis fused bicyclic compounds 11 and 12, respectively.While this intramolecular cycloaddition as a rule occurs at room temperature, the formation of compounds 17/18 and/or 20/21 from the corresponding nitrones needs refluxing in toluene with exception of 17Ca.The N-aryl-substituted nitrones 14C/15C form dimers 22C/23C spontanously at room temperature.However, dimerization is reversible; thus 22/23C afford the bicyclic compounds 17/18 and/or 20/21 on heating in toluene via the corresponding nitrone intermediates. - Hydrogenation cleaves isoxazolidine ring of the bicyclic compounds.Thus, 17Ca and 18Ca yield the hexahydrothiepine 27C and oxepane derivatives 28C, respectively, 21Ca gives the tetrahydropyran 30C.Diastereomerically pure 29C arises by prolonged hydrogenation of 17Ca under reinforced conditions via 27C.
