Hypoxia Activated Prodrugs of a 9-Aza-anthrapyrazole Derivative That Has Promising Anticancer Activity

Abstract

Mono- and bis-N-oxides of a 9-aza-anthrapyrazole derivative having two 2-(dimethylamino)ethyl appendages were prepared by using a mild oxaziridine reagent. Biochemical and cell culture assays indicate that the bis-oxide is an inactive prodrug that readily converts to the active parent molecule under hypoxic conditions that are analogous to those present within certain tumors.

Hypoxia-targeted drug delivery

“…Multi-ring scaffolds, such as 9-aminoacridine (153), [464][465][466] naphthalamide (155 and 156), 467 anthrapyrazole (159), 468 azaanthrapyrazole (160), 469 and mitoxantrone (161), 470 have been explored as hypoxia-selective prodrugs. These systems were generally prepared by appending tertiary N-oxides to the corresponding amines ( viz., 154, 157, 158, and 162; Fig.…”

A ChemoEnzymatic Approach for the Preparation of “Linear‐Shaped” Diaryl Pyrazines as Potential Antiprotozoal Agents

“…Starting from the para ‐halogenated pyrazines 6 and 7 , aromatic nucleophilic substitutions using N′ , N′ ‐dimethyl‐alkyl‐1,n‐diamines or CN − salts (precursor of amidine groups) [20,21] as the nucleophiles were investigated. Different literature protocols, selected by substrate similarity as such reaction was never reported on these scaffolds, were thus applied on the pyrazines 6 and 7 [45–47] . Unfortunately, none of the conditions tested led to the formation of the desired compounds.…”

“…Different literature protocols, selected by substrate similarity as such reaction was never reported on these scaffolds, were thus applied on the pyrazines 6 and 7. [45][46][47] Unfortunately, none of the conditions tested led to the formation of the desired compounds.…”

Synthesis and Evaluation of PPARδ Agonists That Promote Osteogenesis in a Human Mesenchymal Stem Cell Culture and in a Mouse Model of Human Osteoporosis

“…The latter can complicate PK profiling because the S atom becomes asymmetric, whereas the dealkylated metabolite could contribute to toxicity because of the resulting aryl-sulfhydryl group’s inherent reactivity . The dealkylated metabolite also sets up the possibility for it to form a sulfur version of the even more reactive para -quinone-type chemical species upon the loss of acetic acid (Figure B, upper arrows) via a pathway that could initially involve the transient formation of the acid’s tautomer . Initial rescue from such reactive intermediates in mammals by glutathione can be compromised by acute overdose or by continual exposure in sensitive tissues, the latter potentially making a relevant association with cardarine’s carcinogenicity being observed only after long-term dosing. , …”

“…TLC R f (25% EtOAc/hexane) = 0.58.Hz), 7.71 (2H, d, J = 8.6 Hz), 7.62 (1H, d, J = 15.9 Hz), 7.44 (2H, d, J = 8.9 Hz), 6.83 (2H, d, J = 8.9 Hz), 6.24 (1H, d, J = 15.8 Hz), 4.66 (2H, s), 4.24 (2H, q, J = 7.1 Hz), 3.09 (3H, s), 2.32 (3H, s), 1.32 (3H, t, J = 7.1 Hz) 13. C NMR (CDCl 3 , 150 MHz): δ 167.89, 150.80, 145.39, 144.86, 141.96, 129.87, 128.84 (q, 2 J FC = 33 Hz), 126.69 (q, FC = 3.5 Hz), 124.06 (q, 1 J FC = 270 Hz), 123 55,. 118.34, 113.57, 112.76, 60.29, 47.55, 38.71, 14.54, 10.71.…”