Synthesis and Quantitative Structure–Activity Relationship of Imidazotetrazine Prodrugs with Activity Independent of O6-Methylguanine-DNA-methyltransferase, DNA Mismatch Repair and p53.

The antitumor prodrug Temozolomide is compromised by its dependence for activity on DNA mismatch repair (MMR) and the repair of the chemosensitive DNA lesion, O6-methylguanine (O6-MeG), by O6-methylguanine-DNA-methyltransferase (EC 2.1.1.63, MGMT). Tumor response is also dependent on wild-type p53. Novel 3-(2-anilinoethyl)-substituted imidazotetrazines are reported that have activity independent of MGMT, MMR and p53. This is achieved through a switch of mechanism so that bioactivity derives from imidazotetrazine-generated arylaziridinium ions that principally modify guanine-N7 sites on DNA. Mono- and bi-functional analogs are reported and a quantitative structure-activity relationship (QSAR) study identified the p-tolyl-substituted bi-functional congener as optimized for potency, MGMT-independence and MMR-independence. NCI60 data show the tumor cell response is distinct from other imidazotetrazines and DNA-guanine-N7 active agents such as nitrogen mustards and cisplatin. The new imidazotetrazine compounds are promising agents for further development and their improved in vitro activity validates the principles on which they were designed

Microwave-assisted Single-step Synthesis of Acid Hydrazides From Corresponding Acids Utilizing Newly Designed Apparatus

Acid hydrazides are essential intermediates in organic synthesis. They conventionally require a two-step synthetic pathway; esterification and hydrazine hydrate treatment; to obtain the hydrazide. The microwave-assisted synthetic methodology was utilized as a greener and straightforward single-step approach for their synthesis in highly encouraging yields. Thus, the aim of the present work was to synthesize acid hydrazides of Diclofenac, Indomethacin, Ibuprofen, and Mefenamic acid using microwave radiation with the aid of a newly designed fit-in ice condenser. Esters of the selected compounds were firstly synthesized, and acid hydrazides were then synthesized utilizing both the conventional and the proposed microwave-assisted single-step methods. The developed technique was successfully yielded 86.7%, 40.9%, and 65.5% acid hydrazides of Diclofenac, Indomethacin, and Mefenamic acid in just 3 min., 10 min. and 3 min., respectively. In comparison to the conventional method, the developed method was simpler with a very short reaction time and quantified yields. The structures of the synthesized acid hydrazides were also confirmed using FT-IR and 1H-NMR. The proposed method with the modified fit-in ice condenser proved to be efficient, cost-effective, and time-saving in the synthesis of acid hydrazides understudy in a single step