The DARK Side of Total Synthesis: Strategies and Tactics in Psychoactive Drug Production.

Humankind has used and abused psychoactive drugs for millennia. Formally, a psychoactive drug is any agent that alters cognition and mood. The term "psychotropic drug" is neutral and describes the entire class of substrates, licit and illicit, of interest to governmental drug policy. While these drugs are prescribed for issues ranging from pain management to anxiety, they are also used recreationally. In fact, the current opioid epidemic is the deadliest drug crisis in American history. While the topic is highly politicized with racial, gender, and socioeconomic elements, there is no denying the toll drug mis- and overuse is taking on this country. Overdose, fueled by opioids, is the leading cause of death for Americans under 50 years of age, killing ca. 64,000 people in 2016. From a chemistry standpoint, the question is in what ways, if any, did organic chemists contribute to this problem? In this targeted review, we provide brief historical accounts of the main classes of psychoactive drugs and discuss several foundational total syntheses that ultimately provide the groundwork for producing these molecules in academic, industrial, and clandestine settings.

Design, Synthesis and Evaluation of Novel 2-Hydroxypyrrolobenzodiazepine-5,11-dione Analogues as Potent Angiotensin Converting Enzyme (ACE) Inhibitors.

Under the guidance of combination of traditional Chinese medicine chemistry (CTCMC), this study describes the preparation of a phenolic acid/dipeptide/borneol hybrid consisting of phenolic acid and a bornyl moiety connected to the dipeptide N-terminal and C-terminal respectively. It also evaluates their angiotensin converting enzyme (ACE) inhibitory and synergistic antihypertensive activities. Briefly, a series of novel 2-hydroxypyrrolobenzodiazepine-5,11-dione analogues were prepared and investigated for their ability to inhibit ACE. The influence of the phenolic acid and bornyl moiety on subsite selectivity is also demonstrated. Among all the new compounds, two compounds-7a and 7g-reveal good inhibition potency in in vitro ACE-inhibitory tests. Interestingly, favorable binding results in molecular docking studies also supported the in vitro results. Additionally, the bioassay showed that oral administration of the two compounds displayed high and long-lasting antihypertensive activity both in acute antihypertensive tests and in therapeutic antihypertensive tests by non-invasive blood pressure measurements in spontaneously hypertensive rats.

Characterization of the anxiolytic and sedative profile of JM-20: a novel benzodiazepine-dihydropyridine hybrid molecule.

OBJECTIVES: The aim of this study was to investigate the effects of oral administration of a novel benzodiazepine derivative, JM-20, on the neurological behavior of different rodent models, focusing on the GABAergic effect. We have also investigated the acute toxicity of oral administration of JM-20 in mice. METHODS: Mice or rats received oral administration of JM-20 at 2, 4, 8, and 10 mg/kg to evaluate the sedative/hypnotic, anxiolytic, and anticonvulsant effects, as well as the influence on the stereotyped behavior induced by amphetamine. Diazepam (DZP) was used as a positive control. In addition, the mice received a single oral JM-20 dose of 2000 mg/kg to evaluate the acute toxicity. RESULTS: In a dose-dependent manner, JM-20 (i) increased the number of crossings and decreased the number of rearings in the open-field test; (ii) decreased the aggressive behavior of socially-isolated mice; and (iii) increased the latency period for tonic seizure's onset and the percentage of survival of animals with seizures. Moreover, JM-20 increased the sleeping time induced by barbiturates and the time spent and the number of entries in the open arms of the elevated plus-maze test. In the JM-20 toxicity test, no mortality was observed and only minor signs of toxicity associated with sedation were detected. CONCLUSIONS: These results indicate that JM-20 has an anxiolytic profile similar to DZP and its dihydropyridine moiety did not appear to interfere with the GABAergic activity associated with benzodiazepine. Furthermore, JM-20 did not show significant acute toxic effects in mice.

Synthesis and biological evaluation of anilino substituted pyrimidine linked pyrrolobenzodiazepines as potential anticancer agents.

A series of new anilino substituted pyrimidine linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates were prepared and evaluated for their anticancer activity. The effects of four promising PBD conjugates on cell cycle of cancerous cell line A375 were investigated. These compounds showed the characteristic features of apoptosis like enhancement in the levels of p53, release of cytochrome c, and cleavage of PARP.

Optimized synthesis of AMPA receptor antagonist ZK 187638 and neurobehavioral activity in a mouse model of neuronal ceroid lipofuscinosis.

Previous structure-activity relationship studies in the search for a potent, noncompetitive alpha-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist led to 2,3-dimethyl-6-phenyl-12H-[1,3]dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine (ZK 187638). However, the first synthesis had some drawbacks regarding reagents, processes, and overall yield, which furthermore decreased when the synthesis was scaled up. Therefore, we now report a new synthetic route for this compound which requires fewer steps and is suited for large-scale production. This compound significantly relieved the symptoms of neuromuscular deficit in mnd mice, a model of neuronal ceroid lipofuscinosis with motor neuron dysfunction. After oral administration, the concentrations of the compound in the brain and spinal cord were about threefold higher than those in the plasma. In summary, this novel AMPA antagonist is accessible through an optimized synthetic route, has good neurobehavioral activity, oral bioavailability, and favorable brain penetration. This opens new possibilities for the treatment of devastating neurological diseases that are mediated by the AMPA receptor.

Identification of cytotoxic, T-cell-selective 1,4-benzodiazepine-2,5-diones.

A family of 1,4-benzodiazepine-2,5-diones (BZDs) has been synthesized and evaluated against transformed B- and T-cells for lymphotoxic members. A large aromatic group on the C3 position is critical for cytotoxicity. When the C3 moiety contains an electron-rich heterocycle, the resulting BZDs have sub-micromolar potency and are selective for T-cells. Cell death is consistent with apoptosis and does not result from inhibition of the mitochondrial F(o)F1-ATPase, which is the molecular target of recently reported cytotoxic 1,4-benzodiazepines. Collectively, these studies begin to characterize some of the structural elements required for the activity of a novel family of T-cell-selective lymphotoxic agents.

Synthesis of some new substituted triazolo [4,3-a][1,4] benzodiazepine derivatives as potent anticonvulsants.

Novel 8-chloro-6-(2-fluorophenyl)-1-(aryl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepines (5a-f) were prepared by treating 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-thione with various aromatic acid hydrazides. The newly prepared compounds were characterized by spectral analysis. Compounds were tested for anticonvulsant activity. Four of the tested compounds such as 5a, 5d, 5e and 5f exhibited excellent anticonvulsant activity in comparison with standard drug, diazepam.

Potential metabolites of a condensed 2,3-benzodiazepine derivative.

Putative metabolites of an AMPA antagonist imidazo-2,3-benzodiazepine (2) were synthesized and compared to constituents formed from the parent compound by a rat liver perfusion method. As metabolic transformations, hydroxylation of the 2-methyl group and N-acetylation of the amino functionality in parent compound (2) were registered. The hydroxylated analogue 12 of 2 exhibits a weak AMPA antagonist activity.

Synthesis and evaluation of a triplex-forming oligonucleotide-pyrrolobenzodiazepine conjugate.

In most cases, unmodified oligonucleotides designed as antigene molecules are incapable of binding to DNA with sufficient stability to prevent gene expression. To stabilize binding to a polypurine tract in the HER-2/neu promoter, a triplex forming oligonucleotide (TFO) was conjugated to a pyrrolo[1,4]benzodiazepine (PBD), desmethyltomaymycin, and site-specific DNA binding was evaluated. An activated ester of the PBD moiety was conjugated by an acylation reaction to a free primary amine on a 50-atom aliphatic linker at the 5' end of the TFO. This long aliphatic linker was designed to provide a bridge from the major groove binding site of the TFO to the minor groove binding site of the PBD. Triplex formation by the resulting TFO-PBD conjugate occurred more slowly and with a nearly 30-fold lower affinity compared to an unconjugated TFO. PBD binding to the triplex target was demonstrated by protection from restriction enzyme digestion, and covalent binding to the exocyclic amino group of guanine was inferred by substituting specific guanines with inosines. Although the binding of the TFO was less efficient, this report demonstrates that in principle, TFOs can be used to direct the binding of a PBD to specific location. Further optimization of TFO-PBD conjugate design, likely involving optimization of the linker and perhaps placing a PBD at both ends of the TFO, will be needed to make gene modification robust.

Synthesis and pharmacological properties of new 3-ethoxycarbonyl-11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepines.

A series of new 3-ethoxycarbonyl-11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepines was synthesized starting from the corresponding bicyclic 1-aryl-3,5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-ones (CFMs), previously described as noncompetitive AMPA-type glutamate receptor antagonists, more potent than GYKI 52466. New synthesized compounds proved to be able to protect against seizures induced by means of auditory stimulation in DBA/2 mice and compound 8f the most active of the series showed anticonvulsant properties comparable to GYKI 52466.

Identification of a potent and selective oxytocin antagonist, from screening a fully encoded differential release combinatorial chemical library.

A library of 1,296 1,4-benzodiazepines was prepared on 160 microM Tentagel beads. Compounds are attached to the beads using orthogonally cleavable linkers. The library was first screened as pools of 30 beads where 50% of the material is released and screened. GW405212X, a selective oxytocin antagonist, was identified by picking single beads from active pools.

Synthesis and evaluation of pharmacological and pharmacokinetic properties of 11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepin-3(2H)-ones.

A series of 2,3-benzodiazepine derivatives has been previously described as noncompetitive AMPA-type glutamate receptor antagonists potentially useful for treatment of epilepsy. To further explore the structure-activity relationships of AMPA antagonists, a series of 11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepin-3(2H)-ones (6) was synthesized starting from the corresponding bicyclic 1-aryl-3, 5-dihydro-7,8-dimethoxy-4H-2,3-benzodiazepin-4-ones (2, CFM). The new compounds were found to possess anticonvulsant effects against seizures induced both by means of auditory stimulation in DBA/2 mice and by pentylenetetrazole or maximal electroshock in Swiss mice. In addition, they antagonize the AMPA-induced seizures, and their anticonvulsant activity is reversed by pretreatment with aniracetam, thus suggesting the involvement of AMPA receptors. The pharmacological studies revealed that the 11H-[1,2,4]triazolo[4, 5-c][2,3]benzodiazepin-3(2H)-ones (6) herein reported show anticonvulsant activity comparable to that of their bicyclic precursors. Furthermore, an HPLC study put in evidence that these tricyclic derivatives 6 were converted in vivo into the corresponding 2, the agents likely to be mainly responsible for the anticonvulsant properties observed.

3,5-Dihydro-4H-2,3-benzodiazepine-4-thiones: a new class of AMPA receptor antagonists.

Synthesis and evaluation of anticonvulsant activity of a series of 2,3-benzodiazepin-4-ones (2) chemically related to 1-(4'-aminophenyl)-4-methyl-7,8-(methylenedioxy)-5H-2,3-benzodiazepine (1, GYKI 52466) have been reported in our recent publications. Compounds 2 manifested marked anticonvulsant properties acting as 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptor antagonists. In an attempt to better define the structure-activity relationships (SAR) and to obtain more potent and selective anticonvulsant agents, 1-aryl-3,5-dihydro-4H-2, 3-benzodiazepine-4-thiones 3 were synthesized from the corresponding isosteres 2. The evaluation is reported of their anticonvulsant effects, both in the audiogenic seizures test with DBA/2 mice and against the maximal electroshock- and pentylenetetrazole-induced seizures in Swiss mice. New derivatives 3 showed higher potency, less toxicity and longer-lasting anticonvulsant action than those of the parent compounds 2 in all tests employed. Analogous to derivatives 2, new compounds 3 do not affect the benzodiazepine receptor (BZR) while they do antagonize AMPA-induced seizures; their anticonvulsant activity is reversed by pretreatment with aniracetam but not with flumazenil, thus suggesting a clear involvement of AMPA receptors. Electrophysiological data indicate a noncompetitive blocking mechanism at the AMPA receptor sites for 3i, the most active of the series and over 5-fold more potent than 1.