Pyrrolo[2′,3′:3,4]cyclohepta[1,2-d][1,2]oxazoles, a New Class of Antimitotic Agents Active against Multiple Malignant Cell Types

Abstract

A new class of pyrrolo[2′,3′:3,4]cyclohepta[1,2- d ][1,2]oxazoles was synthesized for the treatment of hyperproliferative pathologies, including neoplasms. The new compounds were screened in the 60 human cancer cell lines of the NCI drug screen and showed potent activity with GI 50 values reaching the nanomolar level, with mean graph midpoints of 0.08–0.41 μM. All compounds were further tested on six lymphoma cell lines, and eight showed potent growth inhibitory effects with IC 50 values lower than 500 nM. Mechanism of action studies showed the ability of the new [1,2]oxazoles to arrest cells in the G2/M phase in a concentration dependent manner and to induce apoptosis through the mitochondrial pathway. The most active compounds inhibited tubulin polymerization, with IC 50 values of 1.9–8.2 μM, and appeared to bind to the colchicine site. The G2/M arrest was accompanied by apoptosis, mitochondrial depolarization, generation of reactive oxygen species, and PARP cleavage.

Marine Pyrrole Alkaloids

“…Among the marine alkaloids, which are largely composed of nitrogen-containing heterocycles, the pyrroles form a large group of intriguing natural products which occur in marine organisms ranging from microbes over algae and sponges to animals. Their structural diversity including terpenoid-, polyketide-, carbohydrate-, lipid-, and peptideframeworks [7,12] accompanied by attractive biological properties, has spurred a considerable interest of chemists [6,[13][14][15][16][17][18][19].…”

Marine Power on Cancer: Drugs, Lead Compounds, and Mechanisms

“…Cancer has been the second leading cause of mortality worldwide, causing approximately 10 million deaths in 2020 [ 6 ]. In the past decades, substantial efforts have been made to unveil the pathogenesis of cancers and new anticancer drugs have been developed [ 7 , 8 , 9 , 10 ]. Here, we review the original resources, anticancer effects, mechanisms, and clinical applications of selected marine-derived compounds including cytarabine (the first approved marine-derived anticancer drug), eribulin (a microtubule-depolymerizing drug), marizomib (a proteasome inhibitor), plitidepsin (a DNA synthesis inhibitor), trabectedin (a nucleotide drug), adcetris (an antibody drug conjugate), zalypsis (a new DNA binding alkaloid), and the largazole analogue OKI-179 (an HDAC inhibitor) ( Table 1 ).…”

Evaluation of Fused Pyrrolothiazole Systems as Correctors of Mutant CFTR Protein

“…For many years, we have been involved in studies dealing with nitrogen heterocycles and much of our attention has been paid to tricyclic pyrrolo-fused systems [21][22][23][24][25][26][27][28][29][30][31][32]. Based on our past experience, we decided to investigate the effect on corrector activity of the replacement of one thiazole unit with a pyrrole moiety, which could have allowed the incorporation of some common structural features with constrained bithiazoles, aiming at the identification of new correctors.…”