The isolation of the antitumor antibiotic anthramycin in the 1960s prompted extensive research into pyrrolo [1,4]benzodiazepines (PBD) as potential therapeutics for the treatment of cancers. Since then, nearly 60 PBD natural products have been isolated and evaluated with regard to their biological activity. Synthetic studies and total syntheses have enabled access to PBD analogues, culminating in the development of highly potent anticancer agents. This review provides a summary of the occurrence and biological activity of PBD natural products and covers the strategies employed for their total syntheses.

It has been shown that the cyclization of the methyl 2-(2,2,2-trifluoroacetylamino)acrylate arylation product using methyl 4,6-dichloro-2-iodobenzoate gives the corresponding 1-methoxyisoquinoline-3-carboxylic acid ester through loss of water rather than methanol. This feature of the condensation has been used for the synthesis of methyl 1-(tert-butoxycarbonylmethoxy)isoquinoline-3-carboxylate.The isoquinoline-3-carboxylic acid structure has attracted the attention of chemists to this time due to the many variants of its modification at different isoquinoline positions and also the possibility of converting the carboxyl group into esters, amides, and heterocycles. For instance, esters of 2,4,6-substituted isoquinoline-3-carboxylic acids have been used in the development of novel protein kinase inhibitors [1]. Selective inhibition of phosphodiesterase type 5 has been found in a series of 1,4,6,7-substituted isoquinoline-3-carboxylic acids [2]. 1-Arylisoquinoline-3-carboxylic acid dialkylamide PK11195 (ligand of peripheral benzodiazepine receptors) is a known chemical biomarker of neurodegeneration [3]. A recent synthesis of 1-aryl-substituted isoquinolines involves the use of the Suzuki reaction [4] and is now used for the preparation of PK11195 [5] and its analogs [6]. The most suitable starting materials for the Suzuki reaction are 1-halo-substituted isoquinoline-3-carboxylic acid esters which are readily prepared from the corresponding 1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid esters. The main methods for the synthesis of such compounds are condensation of 1-isochromenones with ammonia or with amines [7,8] or the reaction of o-formylbenzoic acids with derivatives of glycine or its cyclic analogs [9][10][11] or with nitrogen-containing Horner-Wadsworth-Emmons reagents [12,13].A more attractive method for the synthesis of 1-oxo-1,2-dihydroisoquinolines has recently appeared, i.e. the tandem Heck reaction [14] of 2-(acetylamino)acrylates with o-iodobenzoic acid esters and their subsequent cyclization [15]. This route has already been used in the preparation of compound PK11195 [5] and also for development of solid-phase synthetic methods [16]. The indicated method allows the preparation of 1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid esters unsubstituted in the benzene ring in 60-65% yields.

The development of novel μ-opioid receptor (MOR) antagonists is one of the main objectives of drug discovery and development. Based on a simplified version of the morphinan scaffold, 3-[3-(phenalkylamino)cyclohexyl]phenol analogs were designed, synthesized, and evaluated for their MOR antagonist activity in vitro and in silico. At the highest concentrations, the compounds decreased by 52% to 75% DAMGOinduced GTPγS stimulation, suggesting that they acted as antagonists. Moreover, Extra-Precision Glide and Generalized-Born Surface Area experiments provided useful information on the nature of the ligand-receptor interactions, indicating a peculiar combination of C-1 stereochemistry and N-substitutions as feasibly essential for MOR-ligand complex stability. Interestingly, compound 9 showed the best experimental binding affinity, the highest antagonist activity, and the finest MOR-ligand complex stability. In silico experiments also revealed that the most promising stereoisomer (1R, 3R, 5S) 9 retained 1,3-cis configuration with phenol ring equatorial oriented. Further studies are needed to better characterize the pharmacodynamics and pharmacokinetic properties of these compounds.[ 3 H]DAMGO binding assay, 3-[3-(phenalkylamino)cyclohexyl]phenols, GTPγS assay, in silico study, MOR antagonists 1 | INTRODUCTION Despite the serious and potentially fatal adverse effects, μ-opioid receptor (MOR) agonists such as morphine, oxycodone, and fentanyl, have been over/misprescribed in recent years, resulting in a dramatic increase in opioid dependence, illegal opioid use, and opioid-related deaths. Opioid antagonists are a class of drugs that bind competitively to one or more of the opioid receptors, present little or no intrinsic activity, and robustly antagonize the effects of receptor agonists. They are utilized as antidotes for opioid overdose (naloxone) and approved for the treatment of opioid and alcohol dependence (naltrexone). Several structural classes have been identified as MOR antagonists with variable

Application of the Heck Reaction for the Synthesis of 1-Alkoxyisoquinoline-3-carboxylic Acids Esters. -The synthesis of isoquinoline-3-carboxylic acid derivatives via Heck reaction and subsequent cyclization is studied. Surprisingly, 1-alkoxyisoquinoline-3-carboxylic acid esters (VI) and (IX) are obtained with acrylate (V) as Heck reactant. The underlying mechanism remains unclear. -(TURE, A.; RUBINA, K.; ROZHKOV, E.; KAUSS*, V.; Chem. Heterocycl.