Syntheses and Cytotoxicities of Quinazolinone-Based Conjugates.

Two novel series of quinazolinone-based hybrids, including quinazolinone-1,3,4-oxadiazoles (10a-l) and quinazolinone-1,3,4-oxadiazole-benzimidazoles (8a-e), were designed and synthesized and their cytotoxic activities against three human cancer cell lines, lung cancer (A549), cervical cancer (HeLa), and breast cancer (MCF-7), were evaluated. The cytotoxic assays revealed that 10i with a lipophilic 4-fluoro-phenyl moiety at the C-2 position of the quinazolinone ring displayed good cytotoxicities against the A549 and MCF-7 cell lines, while 8b-d with the thioether-linked benzimidazole moiety incorporated on the right side of the oxadiazole ring induced comparable stronger activities toward the MCF-7 cell line, relative to the simple two-heterocycle-containing hybrid 10i. These novel quinazolinone-based hybrids could be considered as lead compounds that merit further optimization and development as anti-cancer agents.

Target Design of Novel Histone Deacetylase 6 Selective Inhibitors with 2-Mercaptoquinazolinone as the Cap Moiety.

Epigenetic alterations found in all human cancers are promising targets for anticancer therapy. In this sense, histone deacetylase inhibitors (HDACIs) are interesting anticancer agents that play an important role in the epigenetic regulation of cancer cells. Here, we report 15 novel hydroxamic acid-based histone deacetylase inhibitors with quinazolinone core structures. Five compounds exhibited antiproliferative activity with IC50 values of 3.4-37.8 µM. Compound 8 with a 2-mercaptoquinazolinone cap moiety displayed the highest antiproliferative efficacy against MCF-7 cells. For the HDAC6 target selectivity study, compound 8 displayed an IC50 value of 2.3 µM, which is 29.3 times higher than those of HDAC3, HDAC4, HDAC8, and HDAC11. Western blot assay proved that compound 8 strongly inhibited tubulin acetylation, a substrate of HDAC6. Compound 8 also displayed stronger inhibition activity against HDAC11 than the control drug Belinostat. The inhibitory mechanism of action of compound 8 on HDAC enzymes was then explored using molecular docking study. The data revealed a high binding affinity (-7.92 kcal/mol) of compound 8 toward HDAC6. In addition, dock pose analysis also proved that compound 8 might serve as a potent inhibitor of HDAC11.

A prospective, randomized comparison between ultrasound-guided supraclavicular, infraclavicular, and axillary brachial plexus blocks.

BACKGROUND: This prospective, randomized, observer-blinded study compared ultrasound-guided supraclavicular (SCB), infraclavicular (ICB), and axillary (AXB) brachial plexus blocks for upper extremity surgery of the elbow, forearm, wrist, and hand. METHODS: One hundred twenty patients were randomly allocated to receive an ultrasound-guided SCB (n = 40), ICB (n = 40), or AXB (n = 40). Performance time (defined as the sum of imaging and needling times) and the number of needle passes were recorded during the performance of the block. Subsequently, a blinded observer recorded the onset time, block-related pain scores, success rate (surgical anesthesia), and the incidence of complications. The main outcome variable was the total anesthesia-related time, defined as the sum of performance and onset times. RESULTS: No differences were observed between the 3 groups in terms of total anesthesia-related time (23.1-25.5 mins), success rate (95%-97.5%), block-related pain scores, vascular puncture, and paresthesia. Compared with the supraclavicular and infraclavicular approaches, ultrasound-guided AXBs required a higher number of needle passes (6.1 [SD, 2.0] vs 2.0-2.6 [SD, 1.1-1.8]; both P < or = 0.001), a longer needling time (7.4 mins [SD, 2.2 mins] vs 4.9-5.5 mins [SD, 1.9-4.2 mins]; both P < or = 0.016), and a longer performance time (8.5 mins [SD, 2.3 mins] vs 6.0-6.2 mins [SD, 2.1-4.5 mins]; both P < or = 0.008). Supraclavicular blocks resulted in a higher rate of Horner syndrome (37.5% vs 0%-5%; both P < 0.001). CONCLUSION: Adjunctive ultrasonography results in similar success rates, total anesthesia-related times, and block-related pain scores for the SCB, ICB, and AXB.

A review of approaches and techniques for lower extremity nerve blocks.

PURPOSE: The purpose of this narrative review is to summarize the evidence derived from randomized controlled trials (RCTs) regarding approaches and techniques for lower extremity nerve blocks. SOURCE: Using the MEDLINE (January 1966 to April 2007) and EMBASE (January 1980 to April 2007) databases, medical subject heading (MeSH) terms "lumbosacral plexus", "femoral nerve", "obturator nerve", "saphenous nerve", "sciatic nerve", "peroneal nerve" and "tibial nerve" were searched and combined with the MESH term "nerve block" using the operator "and". Keywords "lumbar plexus", "psoas compartment", "psoas sheath", "sacral plexus", "fascia iliaca", "three-in-one", "3-in-1", "lateral femoral cutaneous", "posterior femoral cutaneous", "ankle" and "ankle block" were also queried and combined with the MESH term "nerve block". The search was limited to RCTs involving human subjects and published in the English language. Forty-six RCTs were identified. PRINCIPAL FINDINGS: Compared to its anterior counterpart (3-in-1 block), the posterior approach to the lumbar plexus is more reliable when anesthesia of the obturator nerve is required. The fascia iliaca compartment block may also represent a better alternative than the 3-in-1 block because of improved efficacy and efficiency (quicker performance time, lower cost). For blockade of the sciatic nerve, the classic transgluteal approach constitutes a reliable method. Due to a potentially shorter time for sciatic nerve electrolocation and catheter placement than for the transgluteal approach, the subgluteal approach should also be considered. Compared to electrolocation of the peroneal nerve, electrostimulation of the tibial nerve may offer a higher success rate especially with the transgluteal and lateral popliteal approaches. Furthermore, when performing sciatic and femoral blocks with low volumes of local anesthetics, a multiple-injection technique should be used. CONCLUSIONS: Published reports of RCTs provide evidence to formulate limited recommendations regarding optimal approaches and techniques for lower limb anesthesia. Further well-designed and meticulously executed RCTs are warranted, particularly in light of new techniques involving ultrasonographic guidance.