In solid tumors, when O(2) partial pressure drops below 10 mmHg, ATP levels rapidly decrease due to the Warburg effect. It is known that certain macrocyclic polyamines catalyze the chemical hydrolysis of ATP with release of inorganic phosphate. Since tumor cells have diminished ATP levels as compared to normal cells, we attempted to deplete cellular ATP with macrocyclic polyamines in an effort to inhibit tumor cell proliferation. Five macrocyclic polyamines, related to the budmunchamine family of alkaloids, were prepared by total synthesis. They were the [17]-N(4) macrocycle 1, the [16]-N(4) macrocycle 20, the [18]-N(4) macrocycle 13, the [20]-N(5) macrocycle 8, and the [13]-N(3) macrocycle 17. Each one of them hydrolyzed ATP in vitro with release of P(i); the largest ring macrocycle 8 was the most efficient catalyst, while the smallest ring macrocycle 17 was the least efficient (P(i) released in these runs was on the order of 40-100 microM). The linear polyamine spermine had no hydrolytic effect on ATP. The macrocycles were found to be cytotoxic when assessed by means of a MTT assay against two human prostate cell lines, DuPro and PC-3, with resultant ID(50) values ranging between 0.5 and 1.8 microM. Colony forming efficiency (CFE) assays performed on DuPro cells, where the macrocycles were used in a concentration range of 1-8 microM, confirmed the cytotoxic effect of each macrocycle. Each killed 3-4 log of DuPro cells. The smallest ring 17 was the least cytotoxic after 24 h of incubation, although after 144 h of incubation it showed significant cytotoxicity at 8 microM. The macrocycles were equally efficient in depleting the intracellular ATP pools; after a 24 h incubation with each macrocycle other than 17 at 1-8 microM concentrations, cellular ATP concentrations were decreased by 3 orders of magnitude. The decrease in ATP levels was more pronounced after a 72 h incubation, when even 17 reduced ATP by 2 orders of magnitude. A linear pentamine of established cytotoxicity was without effect on the ATP pools. The macrocycles depleted almost entirely the intracellular pools of polyamines and were efficiently taken up by cells. A rough correlation could be established between the cytotoxic effect of the macrocyclic polyamines and their ATP-ase like activity in the DuPro cell line. As ATP is a scarce metabolite in cancer cells, where it can only be replenished through the very ATP-inefficient glycolytic pathway; macrocyclic polyamines appear to be promising new anticancer agents.

No abstract

Cannabinoid receptor subtype 2 (CB2) has been shown to be up-regulated in activated microglia and therefore plays an important role in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis and Alzheimer’s disease. The CB2 receptor is therefore considered as a very promising target for therapeutic approaches as well as for imaging. A promising 2-oxoquinoline derivative designated KP23 was synthesized and radiolabeled and its potential as a ligand for PET imaging the CB2 receptor was evaluated. [11C]KP23 was obtained in 10%–25% radiochemical yield (decay corrected) and 99% radiochemical purity. It showed high stability in phosphate buffer, rat and mouse plasma. In vitro autoradiography of rat and mouse spleen slices, as spleen expresses a high physiological expression of CB2 receptors, demonstrated that [11C]KP23 exhibits specific binding towards CB2. High spleen uptake of [11C]KP23 was observed in dynamic in vivo PET studies with Wistar rats. In conclusion, [11C]KP23 showed promising in vitro and in vivo characteristics. Further evaluation with diseased animal model which has higher CB2 expression levels in the brain is warranted.

Keywords: Allylic oxidation / Fragrances / Musk odorants / Structure-activity relationshipsFour new representatives, 18, 23, 29, and 32, of the young family of dienone musks were synthesized by two general routes. The first five-step synthetic route leading to (3E)-4-(2Ј-alkyl-5Ј,5Ј-dimethylcyclopent-1Ј-enyl)but-3-en-2-ones commenced with the enolate alkylation of 2,2-dimethylcyclopentanone (13), either directly with an alkyl halide or through the Reetz tert-alkylation. Subsequent cerium(III)-mediated butynol Grignard reaction, dehydration with sulfuric acid, (E)-selective partial reduction of the triple bond with lithium aluminum hydride, and concluding pyridinium chlorochromate oxidation complemented this route. The second four-step route leading to (3E)-1-acetyl-3-alkylidene-4,4-dimethylcycloalk-1-enes commenced with the Woods-Grignard modification on the vinylogous ester 3-ethoxycyclohex-2-enone (24) employing ethylmagnesium bromide. The product 25 was then gem-6,6-dimethylated by its lithium enolate

Two seco-theaspiranes with pronounced blackcurrant notes, 2-tert-butyl-5-methyl-2-propyl-2,5-dihydrofuran (7) and 2-tert-butyl-5-methyl-2-propyltetrahydrofuran (8), were synthesized by a synthetic sequence consisting of Grignard reaction, Lindlar hydrogenation, and cyclization followed by optional Pd-catalyzed hydrogenation. The sequence was modified for the synthesis of the oxygenated analogs 2-(2¢-tert-butyl-5¢-methyltetrahydrofuran-2¢-yl)propan-2-ol (9) and 3-(2¢-tert-butyl-5¢-methyltetrahydrofuran-2¢-yl)butan-2-one (10). The first modification featured trimethylsilyl ether protection and stepwise construction of the alkyne moiety necessitated by steric hindrance. In the second modification, a but-2-en-2-yl group was utilized as latent 3-hydroxybut-1-en-2-yl functionality, and the steric constraint around the tertiary hydroxy group was exploited to introduce a stereocenter by S N 2 ring closure. As for the parent compounds 7 and 9, the odor of the oxygenated secotheaspiranes was shifted towards a woody tonality. The likediastereomer 9a even had a typical patchouli profile, and the enantiomers 10a and 10b differed significantly in their olfactory properties.