Antileishmanial activity and tubulin polymerization inhibition of podophyllotoxin derivatives on Leishmania infantum.

Leishmania microtubules play an important role not only in cell division, but also in keeping the shape of the parasite and motility of its free-living stages. Microtubules result from the self-assembly of alpha and beta tubulins, two phylogenetically conserved and very abundant eukaryotic proteins in kinetoplastids. The colchicine binding domain has inspired the discovery and development of several drugs currently in clinical use against parasites. However, this domain is less conserved in kinetoplastids and may be selectively targeted by new compounds. This report shows the antileishmanial effect of several series of compounds (53), derived from podophyllotoxin (a natural cyclolignan isolated from rhizomes of Podophyllum spp.) and podophyllic aldehyde, on a transgenic, fluorescence-emitting strain of Leishmania infantum. These compounds were tested on both promastigotes and amastigote-infected mouse splenocytes, and in mammalian - mouse non-infected splenocytes and liver HepG2 cells - in order to determine selective indexes of the drugs. Results obtained with podophyllotoxin derivatives showed that the hydroxyl group at position C-7α was a structural requisite to kill the parasites. On regards podophyllic aldehyde, derivatives with C9-aldehyde group integrated into a bicyclic heterostructure displayed more potent antileishmanial effects and were relatively safe for host cells. Docking studies of podophyllotoxin and podophyllic aldehyde derivatives showed that these compounds share a similar pattern of interaction at the colchicine site of Leishmania tubulin, thus pointing to a common mechanism of action. However, the results obtained suggested that despite tubulin is a remarkable target against leishmaniasis, there is a poor correlation between inhibition of tubulin polymerization and antileishmanial effect of many of the compounds tested, fact that points to alternative pathways to kill the parasites.

Laparoscopy may decrease morbidity and length of stay after elective colon cancer resection, especially in frail patients: results from an observational real-life study.

BACKGROUND: Advantages of laparoscopic approach in colon cancer surgery have been previously demonstrated in controlled, randomized trials and in retrospective analysis of large administrative databases. Nevertheless, evidence of these advantages in prospective, observational studies from real-life settings is scarce. METHODS: This is a prospective, observational study, including a consecutive series of patients that underwent elective colonic resection for cancer in 52 Spanish hospitals. Pre-/intraoperative data, related to patient, tumor, surgical procedure, and hospital, were recorded as well as 60-day post-operative outcomes, including wound infection, complications, anastomotic leak, length of stay, and mortality. A univariate and multivariate analysis was performed to determine the influence of laparoscopy on short-term post-operative outcome. A sub-analysis of the effect of laparoscopy according to patients' pre-operative risk (ASA Score I-II vs. III-IV) was also performed. RESULTS: 2968 patients were included: 44.2% were initially operated by laparoscopy, with a 13.9% conversion rate to laparotomy. At univariate analysis, laparoscopy was associated with a decreased mortality (p = 0.015), morbidity (p < 0.0001), wound infection (p < 0.0001), and post-operative length of stay (p < 0.0001). At multivariate analysis, laparoscopy resulted as an independent protective factor for morbidity (OR 0.7; p = 0.004), wound infection (OR 0.6; p < 0.0001), and length of post-operative stay (Effect-2 days; p < 0.0001), compared to open approach. These advantages were more relevant in high-risk patients (ASA III-IV), even if the majority of them were operated by open approach (67.1%). CONCLUSIONS: In a real-life setting, laparoscopy decreases wound infection rate, post-operative complications, and length of stay, especially in ASA III-IV patients.

Vasorelaxant effects in aortic rings of eight diterpenoids isolated from three Venezuelan plants

Vasorelaxant activity Vasorelaxant effects of eight diterpenoids isolated from three Venezuelan plants [(+)-manool [(+)-labda-8(17),14-dien-13-ol], (+)-manoyl oxide, (+)-2-oxomanoyl oxide, sandaracopimara-8(14), 15-dien-3β, 19-diol, jhanidiol acetate (18-acetoxy-1βhydroxymanoyl oxide), jhanidiol (1β,18-dihydroxymanoyl oxide), ent-kaur-16-en-19ol and grandiflorenic acid (ent-kaur-9(11),16-dien-19-oic acid)] aortic rings were assessed in intact endothelium and endothelium-denuded isolated rat. Thw cumulative addition (10-6 to 10-4 M) of each product were carried out after contraction with phenylephrine (10-6 M). Jhanidiol acetate and ent-kaur-9,16-en-19-oic acid at 10-4 M dose concentration, exhibit the maximal vasorelaxant effect in endothelium-intact rings (51.61 ± 7.62% and 79.27 ± 7.41%, respectively). In endothelium-denuded aortic rings, the maximum vascular response exerted by both compounds was not abolished (64.14 ± 5.64% and 84.84 ± 3.62%, respectively). In denuded aortic rings, the half-maximal inhibitory concentration (IC50) Jhanidiol was obtained by the ethyl less than those obtained in rings endothelium (1.09 × 10-4 vs 7.29 × 10-5 M, respectively), although this difference was not significant. These results suggested that the mechanism behind the vasorelaxant effect of the two diterpene is mediated by endothelium-independent pathways.

Analgesic and anti-inflammatory activity of podophyllotoxin derivatives.

CONTEXT: Podophyllotoxin is a natural product that inhibits the polymerization of tubulin and has served as a prototype for the development of diverse antitumor agents in clinical use, such as etoposide, teniposide and etopophos. Reumacon, another semisynthetic derivative, reached its clinical phase for the treatment of rheumatoid arthritis. OBJECTIVE: This study investigated the analgesic and anti-inflammatory properties of three compound derivatives from podophyllotoxin. MATERIALS AND METHODS: During a phytochemical study performed on Juniperus thurifera Linne (Cupressaceae) leaves, among other products, several cyclolignans, such as podophyllotoxin, deoxypodophyllotoxin, deoxypicropodophyllotoxin and thuriferic acid were isolated. These compounds, obtained afterwards through semisynthesis, were assayed as analgesic and anti-inflammatory agents. Additionally, the cytotoxic activity of thuriferic acid was evaluated in three cancer cell lines, P-388, A-549 and HT-29, and these data were compared with previous cytotoxicity results obtained for the other three compounds. RESULTS: Analgesic activity results showed that deoxypicropodophyllin is as effective as deoxypodophyllotoxin to inhibit nociceptive perception induced by acetic acid in mice (77.8% ± 4.1% and 71.3% ± 6.5%, respectively), while its cytotoxicity [1.01 × 10(-7) (GI50 M)] is 100-fold less. Other set of experiments showed that thuriferic acid, a derivative of podophyllotoxin a thousand times less citotoxic [1.21 × 10(-5) (GI50 M)] than deoxypodophyllotoxin, caused significant inhibition of paw edema development in the carrageenan-induced inflammation test (63.4% ± 3.3%), effect comparable to those of deoxypodophyllotoxin (66.3% ± 4.4%), and the standard drug indomethacin (61.5% ± 2.5%). CONCLUSION: We conclude that deoxypicropodophyllotoxin and thuriferic acid are effective in reducing edema formation. However, deoxypicropodophyllin is more related with analgesic activity than anti-inflammatory effect.

Synthesis and antimitotic and tubulin interaction profiles of novel pinacol derivatives of podophyllotoxins.

Several pinacol derivatives of podophyllotoxins bearing different side chains and functions at C-7 were synthesized through reductive cross-coupling of podophyllotoxone and several aldehydes and ketones. While possessing a hydroxylated chain at C-7, the compounds retained their respective hydroxyl group with either the 7α (podo) or 7ß (epipodo) configuration. Along with pinacols, some C-7 alkylidene and C-7 alkyl derivatives were also prepared. Cytotoxicities against neoplastic cells followed by cell cycle arrest and cellular microtubule disruption were evaluated and mechanistically characterized through tubulin polymerization inhibition and assays of binding to the colchicine site. Compounds of the epipodopinacol (7ß-OH) series behaved similarly to podophyllotoxin in all the assays and proved to be the most potent inhibitors. Significantly, 7α-isopropyl-7-deoxypodophyllotoxin (20), without any hydroxyl function, appeared as a promising lead compound for a novel type of tubulin polymerization inhibitors. Experimental results were in overall agreement with modeling and docking studies performed on representative compounds of each series.