The Cascade Reactions of Indigo with Propargyl Substrates for Heterocyclic and Photophysical Diversity.

The synthesis of structurally diverse heterocycles for chemical space exploration was achieved via the cascade reactions of indigo with propargylic electrophiles. New pyrazinodiindolodione, naphthyridinedione, azepinodiindolone, oxazinoindolone and pyrrolodione products were prepared in one pot reactions by varying the leaving group (-Cl, -Br, -OMs, -OTs) or propargyl terminal functionality (-H, -Me, -Ph, -Ar). Mechanistic and density functional theory studies revealed that the unsaturated propargyl moiety can behave as an electrophile when aromatic terminal substitutions are made, and therefore competes with leaving group substitution for new outcomes. Selected products from the cascade reactions were investigated for their absorption and fluorescence properties, including transient absorption spectroscopy. This revealed polarity dependent excited state relaxation pathways, fluorescence, and triplet formation, thus highlighting these reactions as a means to access diverse functional materials rapidly.

Predictive Factors for Time to Progression after Hyperthermic Mitomycin C Treatment for High-Risk Non-Muscle Invasive Urothelial Carcinoma of the Bladder: An Observational Cohort Study of 97 Patients.

INTRODUCTION: Hyperthermic mitomycin (HM) is a novel treatment modality for selected patients with high-risk non-muscle invasive bladder cancer (NMIBC). We sought to determine predictors of response to this therapy. PATIENTS AND METHODS: A longitudinal, cohort study of 97 patients with high-risk NMIBC treated with ≥4 HM instillations on a prophylactic schedule was conducted. The primary outcome was time-to-progression survival; secondary outcomes were overall survival, cancer-specific survival, and adverse events. Descriptive statistics, Kaplan-Meier survival analyses, Cox proportional hazards modelling, and univariate and multivariable regression were performed. RESULTS: The presence of initial complete response (CR; no evidence of disease at first check video-cystoscopy and urine cytology) post-HM treatment was an independent predictor of good response to HM. Female patients and those without carcinoma in situ (CIS) also appeared to respond better to the intervention. The overall bladder preservation rate at a median of 27 months was 81.4%; 17/97 (17.5%) patients died during the course of the study. CONCLUSIONS: High-risk NMIBC patients can be safely treated with HM and have good oncological outcome. However, those without an initial CR have a poor prognosis and should be counselled towards adopting other treatment methodologies such as cystectomy. Female gender and lack of CIS may be good prognostic indicators for response to HM.

Approaches, Strategies and Procedures for Identifying Anti-Inflammatory Drug Lead Molecules from Natural Products.

Natural products (NPs) have played a vital role in human survival for millennia, particularly for their medicinal properties. Many traditional medicine practices continue to utilise crude plants and animal products for treating various diseases, including inflammation. In contrast, contemporary medicine focuses more on isolating drug-lead compounds from NPs to develop new and better treatment drugs for treating inflammatory disorders such as inflammatory bowel diseases. There is an ongoing search for new drug leads as there is still no cure for many inflammatory conditions. Various approaches and technologies are used in drug discoveries from NPs. This review comprehensively focuses on anti-inflammatory small molecules and describes the key strategies in identifying, extracting, fractionating and isolating small-molecule drug leads. This review also discusses the (i) most used approaches and recently available techniques, including artificial intelligence (AI), (ii) machine learning, and computational approaches in drug discovery; (iii) provides various animal models and cell lines used in in-vitro and in-vivo assessment of the anti-inflammatory potential of NPs.

The In Vitro Antioxidant and Anti-Inflammatory Activities of Selected Australian Seagrasses.

Recent studies have shown that seagrasses could possess potential applications in the treatment of inflammatory disorders. Five seagrass species (Zostera muelleri, Halodule uninervis, Cymodocea rotundata, Syringodium isoetifolium, and Thalassia hemprichii) from the Great Barrier Reef (QLD, Australia) were thus collected, and their preliminary antioxidant and anti-inflammatory activities were evaluated. From the acetone extracts of five seagrass species subjected to 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging antioxidant assay, the extract of Z. muelleri had the highest activity (half minimal concentration of inhibition (IC50) = 138 µg/mL), with the aerial parts (IC50 = 119 µg/mL) possessing significantly higher antioxidant activity than the roots (IC50 ≥ 500 µg/mL). A human peripheral blood mononuclear cells (PBMCs) assay with bacterial lipopolysaccharide (LPS) activation and LEGENDplex cytokine analysis showed that the aerial extract of Z. muelleri significantly reduced the levels of inflammatory cytokines tumour necrosis factor alpha (TNF-α), interleukin (IL)-1ß, and IL-6 by 29%, 74%, and 90%, respectively, relative to the LPS treatment group. The aerial extract was thus fractionated with methanol (MeOH) and hexane fraction, and purification of the MeOH fraction by HPLC led to the isolation of 4-hydroxybenzoic acid (1), luteolin (2), and apigenin (3) as its major constituents. These compounds have been previously shown to reduce levels of TNF-α, IL-1ß, and IL-6 and represent some of the major bioactive components of Z. muelleri aerial parts. This investigation represents the first study of the antioxidant and anti-inflammatory properties of Z. muelleri and the first isolation of small molecules from this species. These results highlight the potential for using seagrasses in treating inflammation and the need for further investigation.

The Ethnopharmacology, Phytochemistry and Bioactivities of the Corymbia Genus (Myrtaceae).

Plants have been vital to human survival for aeons, especially for their unique medicinal properties. Trees of the Eucalyptus genus are well known for their medicinal properties; however, little is known of the ethnopharmacology and bioactivities of their close relatives in the Corymbia genus. Given the current lack of widespread knowledge of the Corymbia genus, this review aims to provide the first summary of the ethnopharmacology, phytochemistry and bioactivities of this genus. The Scopus, Web of Science, PubMed and Google Scholar databases were searched to identify research articles on the biological activities, phytochemistry and ethnomedical uses of Corymbia species. Of the 115 Corymbia species known, 14 species were found to have ethnomedical uses for the leaves, kino and/or bark. Analysis of the references obtained for these 14 Corymbia spp. revealed that the essential oils, crude extracts and compounds isolated from these species possess an array of biological activities including anti-bacterial, anti-fungal, anti-protozoal, anti-viral, larvicidal, insecticidal, acaricidal, anti-inflammatory, anti-oxidant, anti-cancer and anti-diabetic activities, highlighting the potential for this under-studied genus to provide lead compounds and treatments for a host of medical conditions.

An investigation of the allylation cascade reactions of substituted indigos.

In a continuation of the exploration of indigo cascade reactions, a series of -OMe, -Ph, -Br and -NO2 substituted indigos 1a-i were synthesised to probe electronic effects upon the outcome of allylation cascade reactions. When indigos 1a-i in the presence of base were reacted with allyl bromide, spiroindolinepyridoindolones 17-25 (36-75%) were obtained as the major products in each case, marking a shift in outcome relative to that previously reported for unsubstituted indigo. In electron-rich derivatives (-OMe, -Ph), C-allylspiroindolinepyridoindolediones 26-29 (3-11%) were also isolated, which are most likely formed via a Claisen rearrangement of the respective spiroindolinepyridoindolones 18-21. Additionally, the isolation of diallylbiindolone 16, oxazinobiindole 30 and N,N'-diallyl-3,3'-bis(allyloxy)biindole 31 each represented novel polyheterocyclic derivatives, providing intriguing new mechanistic insights, reaction pathways and in the case of 30 the first common heterocyclic skeletal outcome shared in both allylation and propargylation cascade reactions of indigo.

Cystectomy outcomes in patients who have failed Radiofrequency-induced Thermo-chemotherapeutic Effect Mitomycin-C (RITE-MMC) treatment for high-risk non-muscle invasive bladder cancer (HRNMIBC)-Does it complicate surgery and adversely impact oncological outcome?

INTRODUCTION: The standard intravesical treatment for high risk non muscle invasive bladder cancer (HRNMIBC) is Bacillus Calmette-Guérin (BCG), with failure often resulting in cystectomy. Radiofrequency-Induced Thermo-chemotherapeutic Effect Mitomycin (RITE-MMC) can be an alternative in BCG failure. There has been concern that RITE-MMC may delay an inevitable cystectomy, make it more technically challenging and worsen prognosis. The aim of this study was to assess operative challenges and oncological outcome in patients undergoing cystectomy for HRNMIBC who received RITE-MMC, and contrast them with those that did not. PATIENTS AND METHODS: A retrospective study of a prospective cystectomy database was conducted. Patients treated from April 2011 to June 2017 were looked at. Inclusion criteria were HRNMIBC with BCG failure undergoing cystectomy. Patient demographics and tumour characteristics were analysed. Intraoperative blood loss and length of stay were used as surrogate markers for intra-operative difficulty. Kaplan-Meier curves were constructed to analyse all-cause mortality, cancer specific mortality and time to recurrence between the RITE-MMC treatment group and those that did not receive RITE-MMC. A multivariate analysis was conducted to assess factors that may influence readmission. RESULTS: Thirty-six patients who received RITE-MMC underwent cystectomy, compared to 102 that did not. Median ages were comparable at 72 and 69 years, respectively. Patients were followed up for a median of 24 months across the 2 groups. The commonest histological stage in both groups was CIS. There were no significant differences in intraoperative blood loss, length of stay and 90-day readmission between the 2 groups. There were proportionally fewer recurrences in the RITE-MMC group (16% vs. 19%) and median time to recurrence was longer in the RITE-MMC group (37 months vs. 24 months). Multivariate analysis did not reveal a significant correlation between pre-op RITE-MMC and post-operative readmission (P = 0.606). Survival curves show no significant difference in time to recurrence across both groups (P = 0.513), and no overall (P = 0.069) or cancer specific mortality (P = 0.129) dis-advantage was noted in the RITE-MMC group. CONCLUSION: We have found that RITE-MMC treatment does not result in a technically more challenging cystectomy and does not compromise oncological outcome compared to those patients undergoing cystectomy immediately post-BCG failure. We feel RITE-MMC remains a useful tool in a carefully selected group of patients who may not be willing to accept the morbidity of a cystectomy at the time, without significantly compromising their long-term outcome.

Treatment of carcinoma in situ of the glans penis with topical chemotherapy agents.

BACKGROUND: The use of topical agents in the treatment of carcinoma in situ (CIS) of the penis has been well described in the literature. Previous studies have been limited by small sample size and imprecise end points. OBJECTIVE: Establish the response rate of 5-fluorouracil (5-FU) and imiquimod (IQ) in the treatment of penile CIS in a large contemporary series in a supranetwork centre. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of all primary and recurrent cases of penile CIS treated with 5-FU and IQ identified from a prospective database over a 10-yr period. Therapy was standardised in all cases with application to the lesion for 12h every 48 h for 28 d. INTERVENTION: 5-FU was the first-line therapy, and IQ was the second-line topical agent. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was defined as complete response (CR; i.e., resolution of lesion), partial response (PR; i.e., lesion reduced in size and or visibility), or no response (NR; ie, no improvement in lesion size and or visibility). The secondary end points included local toxicity and adverse events. No statistical analysis or software was used. RESULTS AND LIMITATIONS: A total of 86 patients were diagnosed with CIS of the penis over the 10-yr period. Forty-four (51%) received topical chemotherapy. The mean follow-up was 34 mo. CR to topical chemotherapy was seen in 25 (57%), PR was seen in 6 (13.6%), and NR was seen in the remaining 13 (29.5%) patients. Local toxicity was experienced by 10% of patients, and 12% had an adverse event following application of 5-FU. The retrospective design and short follow-up were the major limitations of this study. CONCLUSIONS: Topical chemotherapy agents are moderately effective first-line therapy in the treatment of penile CIS. Toxicity and adverse events were few with our treatment protocol. The issues of long-term surveillance and assessment of partial responders remain a challenge. Topical chemotherapy should remain a first-line treatment option for penile CIS.

Lymph node metastasis in intermediate-risk penile squamous cell cancer: a two-centre experience.

BACKGROUND: The risk of lymph node (LN) metastasis in G2T1 penile cancer has been previously reported as 0-50% and is classified as "intermediate" in the European Association of Urology (EAU) guidelines. The management of impalpable regional nodes in this cohort of patients remains contentious and varies among treatment centres depending on tumour factors and local resources. OBJECTIVES: To establish the risk of LN metastasis in G2T1 disease. DESIGN, SETTINGS, AND PARTICIPANTS: We interrogated the databases of two referral centres for penile cancer. MEASUREMENTS: Out of 902 patients, 117 (13%) patients were identified with G2T1 cancers. Those with palpable inguinal nodes (cN1) underwent early inguinal LN dissection (iLND). Those with clinically node negative (cN0) inguinal basins were either observed or surgically staged with iLND or by dynamic sentinel LN biopsy (DSLNB). Median follow-up was 44 mo, with minimum follow-up of 6 mo. RESULTS AND LIMITATIONS: Fifteen of 117 (13%) patients with G2T1 cancer had LN metastasis at initial staging or during follow-up. Six of 12 (50%) cN1 patients had histologically proven LN metastasis on iLND. One hundred five patients were cN0 at presentation. Ten cN0 patients had prophylactic iLND, none of which yielded LN metastasis; 5 of 64 (8%) cN0 patients who had DSLNB had tumour-positive LNs, and 4 of 31 (13%) cN0 patients who were observed developed LN metastasis during follow-up. In cN0 patients, the risk of LN metastasis at initial staging or during surveillance was 9%. CONCLUSIONS: We consider that in cN0 patients with G2T1 penile cancer, the risk of developing metastases during surveillance warrants surgical and potentially curative staging. However, the morbidity of prophylactic bilateral iLND is too great to justify a detection rate of 9%. Less morbid alternatives such as DSLNB are advisable in G2T1 disease.

Acetabular morphology in bladder exstrophy complex.

Little information is available concerning the acetabular morphology in adults with a history of bladder exstrophy. We documented the pelvic anatomy in adult patients with bladder exstrophy who never had prior surgery. We retrospectively reviewed 31 patients (62 hips) seen from 1976 to 2003 for urologic problems related to bladder exstrophy without adjunctive pelvic osteotomy. There were 18 males and 13 females with an average age of 30 years at last followup. Radiographs at final followup were analyzed for lateral center-edge angle, acetabular index, head extrusion, hip center of rotation, acetabular version, retroversion index, sacral width, and interteardrop distance. Most hips (60 hips) had no arthritis. The average lateral center-edge angle, ace-tabular index, and head extrusion index were 32 degrees, 5.7 degrees, and 0.266%, respectively. Fifty-eight percent of hips had a retroverted acetabulum and 42% were neutral or anteverted. The interteardrop distance averaged 154 mm. Most patients will not have early arthritis develop, and the majority of patients (58%) have retroverted orientation of the acetabulum.

Reconstructive surgery for invasive squamous carcinoma of the glans penis.

OBJECTIVES: We present medium-term outcome data for patients with invasive penile cancer treated with glansectomy and reconstruction with a split-thickness skin graft. METHODS: A series of consecutive patients referred with penile malignancies over a 6-yr period were analyzed prospectively. A dedicated histopathologist reviewed all the specimens. After clinical staging, patients with tumours confined to the glans were offered glansectomy. RESULTS: A total of 72 patients (32% of patients, 31% of procedures) underwent glansectomy for penile carcinoma. Of these, 65 patients were new diagnoses and seven were recurrences after radiotherapy. The mean follow-up period was 27 mo (range: 4-68 mo). There have been three late local recurrences (4%). CONCLUSION: Glansectomy appears to be an oncologically safe and effective procedure for patients with glans-confined squamous cell tumours. It preserves maximum phallic length and results in a very satisfactory cosmetic penile appearance after reconstruction.

Penile-preserving surgery for male distal urethral carcinoma.

OBJECTIVE: To evaluate medium-term outcome data from patients with distal urethral cancers treated with penile-preserving surgery. PATIENTS AND METHODS: We analysed prospectively 18 consecutive men referred for the management of urethral carcinoma. All had a specialist review in a supra-regional multidisciplinary team meeting, where the histology findings were reviewed by one pathology consultant. Tumours were staged according to the Tumour-Node-Metastasis classification and the patients offered penile-preserving surgery when tumours were limited to the glanular or penile urethra. RESULTS: All 18 patients were suitable for penile-preserving surgery; the procedures were: three hypospadias formation with or without topical chemotherapy; four buccal mucosa urethroplasty; three glansectomy and reconstruction; six glansectomy, distal corporectomy, reconstruction and hypospadias formation; two urethrectomy with or with no excision of adjacent tunica albuginea. The mean (median, range) follow-up was 26 (20.5, 9-58) months. There were no local recurrences; four patients with regional nodal disease progressed and of these, two died from metastatic disease, and one died from an unrelated condition. CONCLUSION: Medium-term data show that penile-preserving surgery is a feasible treatment for men with distal urethral carcinoma, providing excellent local control without prejudicing survival; a longer follow-up is needed.