“…2 ), the cyclocondensation of equimolar mixture of L-proline and isatoic anhydride in DMF at 155 °C [ 18 , 19 ] by a standard protocol afforded dilactam 1 which was recrystallized from a 10:1 v/v mixture of acetone and DMF to obtain compound 1 as off white crystals. Thionation of compound 1 with 0.5 equiv Lawesson's reagent in THF at room temperature afforded thiolactam 2 [ 13 , 20 ]. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…The mixture was stirred for further 1 h at this temperature. After cooling to room temperature, the mixture was filtered through a plug of celite and eluted with dichloromethane (CH 2 Cl 2 ) [13] . The filtrate was washed with saturated Na 2 S 2 O 3 and after extraction with CH 2 Cl 2 , the combined organic layers were dried over magnesium sulfate (MgSO 4 ), filtered, and the solvent and excess amine were evaporated under reduced pressure.…”
Section: Methodsmentioning
confidence: 99%
“…In continuation to our previous attempts to discover novel bioactive PBDs and improvement of their efficacy [ 13 , 14 , 15 , 16 ], we became interested in the synthesis and characterization of a new class of tetracyclic PBD derivatives with fused heterocyclic moiety. We evaluated a panel of thirteen novel PBD's for in vitro cytotoxicity using NCI-60 cell lines screening.…”
Cancer remains the second major cause of death in the world. Thus, there is a pressing need to identify potential synthetic route for the development of novel anticancer agents which will serve as lead compounds to effectively combat this life-threatening epidemic. Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) have sparked a great interest as lead compounds because of their cancerostatic and anti-infective properties. The twisted molecular structure of PBD analogs provides both helical and chiral elements. In an effort to expand novel PBDs that interact with the key exocyclic amino group of the DNA-guanine base, we hypothesized that construction of a fused cyclic active system, would likely serve as an electrophilic site when compared to traditional electrophilic C11-N10 imine group. To examine our theory, we report herein the synthesis and cell viability/cytotoxicity of a series of PBD analogs using NCI-60 cell lines screening. Thus, compounds 1–13 were synthesized and fully characterized. The selected PBDs were found to have marginal inhibition of growth, up to 30%, for certain cell lines.
“…2 ), the cyclocondensation of equimolar mixture of L-proline and isatoic anhydride in DMF at 155 °C [ 18 , 19 ] by a standard protocol afforded dilactam 1 which was recrystallized from a 10:1 v/v mixture of acetone and DMF to obtain compound 1 as off white crystals. Thionation of compound 1 with 0.5 equiv Lawesson's reagent in THF at room temperature afforded thiolactam 2 [ 13 , 20 ]. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…The mixture was stirred for further 1 h at this temperature. After cooling to room temperature, the mixture was filtered through a plug of celite and eluted with dichloromethane (CH 2 Cl 2 ) [13] . The filtrate was washed with saturated Na 2 S 2 O 3 and after extraction with CH 2 Cl 2 , the combined organic layers were dried over magnesium sulfate (MgSO 4 ), filtered, and the solvent and excess amine were evaporated under reduced pressure.…”
Section: Methodsmentioning
confidence: 99%
“…In continuation to our previous attempts to discover novel bioactive PBDs and improvement of their efficacy [ 13 , 14 , 15 , 16 ], we became interested in the synthesis and characterization of a new class of tetracyclic PBD derivatives with fused heterocyclic moiety. We evaluated a panel of thirteen novel PBD's for in vitro cytotoxicity using NCI-60 cell lines screening.…”
Cancer remains the second major cause of death in the world. Thus, there is a pressing need to identify potential synthetic route for the development of novel anticancer agents which will serve as lead compounds to effectively combat this life-threatening epidemic. Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) have sparked a great interest as lead compounds because of their cancerostatic and anti-infective properties. The twisted molecular structure of PBD analogs provides both helical and chiral elements. In an effort to expand novel PBDs that interact with the key exocyclic amino group of the DNA-guanine base, we hypothesized that construction of a fused cyclic active system, would likely serve as an electrophilic site when compared to traditional electrophilic C11-N10 imine group. To examine our theory, we report herein the synthesis and cell viability/cytotoxicity of a series of PBD analogs using NCI-60 cell lines screening. Thus, compounds 1–13 were synthesized and fully characterized. The selected PBDs were found to have marginal inhibition of growth, up to 30%, for certain cell lines.
“…Pyrrolo[2,1-c] [1,4]benzodiazepines (PBDs) are a class of natural products known to possess anti-tumor and antibiotic activities [10][11][12]. Molecular modeling studies have shown that the PBD tricyclic structure is well-suited to dock within the catalytic cavity of CB receptors, allowing them to interact with the endocannabinoid signaling system.…”
Modulation of the endocannabinoid system (ECS) is of great interest for its therapeutic relevance in several pathophysiological processes. The CB2 subtype is largely localized to immune effectors, including microglia within the central nervous system, where it promotes anti-inflammation. Recently, a rational drug design toward precise modulation of the CB2 active site revealed the novelty of Pyrrolo[2,1-c][1,4]benzodiazepines tricyclic chemotype with a high conformational similarity in comparison to the existing leads. These compounds are structurally unique, confirming their chemotype novelty. In our continuing search for new chemotypes as selective CB2 regulatory molecules, following SAR approaches, a total of 17 selected (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs were synthesized and tested for their ability to bind to the CB1 and CB2 receptor orthosteric sites. A competitive [3H]CP-55,940 binding screen revealed five compounds that exhibited >60% displacement at 10 μM concentration. Further concentration-response analysis revealed two compounds, 4k and 4q, as potent and selective CB2 ligands with sub-micromolar activities (Ki = 146 nM and 137 nM, respectively). In order to support the potential efficacy and safety of the analogs, the oral and intravenous pharmacokinetic properties of compound 4k were sought. Compound 4k was orally bioavailable, reaching maximum brain concentrations of 602 ± 162 ng/g (p.o.) with an elimination half-life of 22.9 ± 3.73 h. Whether administered via the oral or intravenous route, the elimination half-lives ranged between 9.3 and 16.7 h in the liver and kidneys. These compounds represent novel chemotypes, which can be further optimized for improved affinity and selectivity toward the CB2 receptor.
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