Chemical Profiling of Medical Cannabis Extracts

Medical cannabis has been legally available for patients in a number of countries. Licensed producers produce a variety of cannabis strains with different concentrations of phytocannabinoids. Phytocannabinoids in medical cannabis are decarboxylated when subjected to heating for consumption by the patients or when extracted for preparing cannabis derivative products. There is little understanding of the true chemical composition of cannabis extracts, changes occurring during heating of the extracts, and their relevance to pharmacological effects. We investigated the extract from a popular commercial strain of medical cannabis, prior to and after decarboxylation, to understand the chemical profiles. A total of up to 62 compounds could be identified simultaneously in the extract derived from commercial cannabis, including up to 23 phytocannabinoids. Upon heating, several chemical changes take place, including the loss of carboxylic group from the acidic phytocannabinoids. This investigation attempts to reveal the chemical complexity of commercial medical cannabis extracts and the differences in the chemical composition of the native extract and the one subjected to heat. Comprehensive chemical analyses of medical cannabis extracts are needed for standardization, consistency, and, more importantly, an informed employment of this substance for therapeutic purposes

Interrogation of the Active Sites of Protein Arginine Deiminases (PAD1, -2, and -4) Using Designer Probes

Protein arginine deiminases (PADs) are involved in a number of cellular pathways, and they catalyze the transformation of peptidyl arginine residue into a citrulline as part of post-translational modifications. To understand ligand preferences, a group of probe molecules were investigated against PAD1, PAD2, and PAD4. These probe molecules carried a well-known covalent modifier of the catalytic cysteine residue, 2-chloroacetamidine moiety, which was tethered to an α-amino acid via a carbon linker. The chain length for the linker varied from 0 to 4. Time-dependent assays indicated that 2-chloroacetamidine (2CA) with no linker inhibited all PAD enzymes with a similar trend in the second-order rate constants, although with poor affinity. Among the other three probe molecules, compound <b>3</b> with a three-carbon linker exhibited the best second-order rate constants for optimal ligand reactivity with the binding site. These analyses provide insights into the relative patterns of covalent inactivation of PAD isozymes and the design of novel inhibitors targeting PAD enzymes as potential therapeutic targets

Noncovalent Protein Arginine Deiminase (PAD) Inhibitors Are Efficacious in Animal Models of Multiple Sclerosis

Peptidyl arginine deiminases have been shown to be hyperactive in neurodegenerative diseases including multiple sclerosis. An α-amino acid-based core structure, derived from a hydantoin core, with unique heterocycles on the side chains were synthesized as potential noncovalent inhibitors of PAD enzymes. Among the various heterocycles investigated, compound <b>23</b>, carrying an imidazole moiety, exhibited the highest potency in this series with some selectivity for PAD2, and was further investigated in vivo. Pharmacokinetics in mice suggested the <i>C</i>_max to be 12.0 ± 2.5 μg/mL and 170 ± 10 ng/mL in the serum and brain, respectively, when compound <b>23</b> was administered at 50 mg/kg via single dose ip. At the same dose, compound <b>23</b> also reversed physical disability and cleared the brain of T-cell infiltration in an EAE mouse model of multiple sclerosis (MS). This novel series of compounds show promise for further development as disease modifying agents for the potential treatment of MS

Noncovalent Protein Arginine Deiminase (PAD) Inhibitors Are Efficacious in Animal Models of Multiple Sclerosis

Peptidyl arginine deiminases have been shown to be hyperactive in neurodegenerative diseases including multiple sclerosis. An α-amino acid-based core structure, derived from a hydantoin core, with unique heterocycles on the side chains were synthesized as potential noncovalent inhibitors of PAD enzymes. Among the various heterocycles investigated, compound <b>23</b>, carrying an imidazole moiety, exhibited the highest potency in this series with some selectivity for PAD2, and was further investigated in vivo. Pharmacokinetics in mice suggested the <i>C</i>_max to be 12.0 ± 2.5 μg/mL and 170 ± 10 ng/mL in the serum and brain, respectively, when compound <b>23</b> was administered at 50 mg/kg via single dose ip. At the same dose, compound <b>23</b> also reversed physical disability and cleared the brain of T-cell infiltration in an EAE mouse model of multiple sclerosis (MS). This novel series of compounds show promise for further development as disease modifying agents for the potential treatment of MS

Antimalarial Activities of 6‑Iodouridine and Its Prodrugs and Potential for Combination Therapy

Resistance by <i>Plasmodium falciparum</i> to almost all clinically used antimalarial drugs requires the development of new classes of antimalarials. 6-Iodouridine (<b>15</b>), a novel and potent inhibitor of orotidine 5′-monophosphate decarboxylase (ODCase), exhibited efficacy in a mouse model infected by <i>P. chabaudi chabaudi</i>. Compound <b>15</b> exhibited promising antimalarial activity against <i>P. falciparum</i>, including drug-resistant isolates, and no rapid drug-resistant populations of the parasite were observed when challenged with <b>15</b>. Uridine provided options to overcome any toxicity in the host but still suppressing the parasite load when treated with <b>15</b>. In drug combination studies, compound <b>15</b> showed good efficacy in vivo with artemisinin and azithromycin. The propionyl ester of <b>15</b> exhibited superior antimalarial efficacy. Antimalarial activities of <b>15</b> and its prodrugs and potential for combination therapy are discussed in the context of novel strategies