The synthesis of strained carbocyclic building blocks is relevant for Medicinal Chemistry, and methylenecyclobutanes are particularly challenging with current synthetic technology. Careful inspection of the reactivity of [1.1.1]propellane and diboron reagents has revealed that bis(catecholato)diboron (B2cat2) can produce a bis(borylated) methylenecyclobutane in a few minutes at room temperature. This reaction constitutes the first example of B-B bond activation by a special apolar hydrocarbon and also the first time that propellane is electrophilically activated by boron. Mechanistic studies including in situ NMR kinetics and DFT calculations demonstrate that the diboron moiety can be directly activated through coordination with the inverted sigma bond of propellane, and reveal that DMF is involved in the stabilization of diboronate ylide intermediates rather than the activation of the B-B bond. These results enable new possibilities for both diboron and propellane chemistry, and for further developments in the synthesis of methylenecyclobutanes based on propellane strain release.

BACKGROUND: Previous studies have shown that the addition of platinum to neoadjuvant chemotherapy (NAC) improved outcomes for patients with triple-negative breast cancer (TNBC). However, no studies have assessed the efficacy and safety of the combination of taxane and lobaplatin. In this study, we conducted a randomized controlled phase II clinical study to compare the efficacy and safety of taxane combined with lobaplatin or anthracycline.
METHODS: We randomly allocated patients with stage I-III TNBC into Arm A and Arm B. Arm A received six cycles of taxane combined with lobaplatin (TL). Arm B received six cycles of taxane combined with anthracycline and cyclophosphamide (TEC) or eight cycles of anthracycline combined with cyclophosphamide and sequential use of taxane (EC-T). Both Arms underwent surgery after NAC. The primary endpoint was the pathologic complete response (pCR). Secondary endpoints were event-free survival (EFS), overall survival (OS), and safety.
RESULTS: A total of 103 patients (51 in Arm A and 52 in Arm B) were assessed. The pCR rate of Arm A was significantly higher than that of Arm B (41.2% vs. 21.2%, P = 0.028). Patients with positive lymph nodes and low neutrophil-to-lymphocyte ratio (NLR) benefited significantly more from Arm A than those with negative lymph nodes and high NLR (Pinteraction = 0.001, Pinteraction = 0.012, respectively). There was no significant difference in EFS (P = 0.895) or OS (P = 0.633) between the two arms. The prevalence of grade-3/4 anemia was higher in Arm A (P = 0.015), and the prevalence of grade-3/4 neutropenia was higher in Arm B (P = 0.044).
CONCLUSIONS: Neoadjuvant taxane plus lobaplatin has shown better efficacy than taxane plus anthracycline, and both regimens have similar toxicity profiles. This trial may provide a reference for a better combination strategy of immunotherapy in NAC for TNBC in the future.

BACKGROUND: The early identification of responsive and resistant patients to androgen receptor-targeting agents (ARTA) in metastatic castration-resistant prostate cancer (mCRPC) is not completely possible with prostate-specific antigen (PSA) assessment and conventional imaging. Considering its ability to determine metabolic activity of lesions, positron emission tomography (PET) assessment might be a promising tool.
METHODS: We carried out a monocentric prospective study in patients with mCRPC treated with ARTA to evaluate the role of different PET radiotracers: 49 patients were randomized to receive 11C-Choline, Fluorine 18 fluciclovine (anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid - FACBC) (18F-FACBC), or Gallium-68-prostate-specific-membrane-antigen (68Ga-PSMA) PET, one scan before therapy and one 2 months later. The primary aim was to investigate the performance of three novel PET radiotracers for the early evaluation of response to ARTA in metastatic CRPC patients; the outcome evaluated was biochemical response (PSA reduction ≥50%). The secondary aim was to investigate the prognostic role of several semiquantitative PET parameters and their variations with the different radiotracers in terms of biochemical progression-free survival (bPFS) and overall survival (OS). The study was promoted by the Italian Department of Health (code RF-2016-02364809).
RESULTS: Regarding the primary endpoint, at log-rank test a statistically significant correlation was found between metabolic tumor volume (MTV) (P = 0.018) and total lesion activity (TLA) (P = 0.025) percentage variation among the two scans with 68Ga-PSMA PET and biochemical response. As for the secondary endpoints, significant correlations with bPFS were found for 68Ga-PSMA total MTV and TLA at the first scan (P = 0.001 and P = 0.025, respectively), and MTV percentage variation (P = 0.031). For OS, statistically significant correlations were found for different 68Ga-PSMA and 18F-FACBC parameters and for major maximum standardized uptake value at the first 11C-Choline PET scan.
CONCLUSIONS: Our study highlighted that 11C-Choline, 68Ga-PSMA, and 18F-FACBC semiquantitative PET parameters and their variations present a prognostic value in terms of OS and bPFS, and MTV and TLA variations with 68Ga-PSMA PET a correlation with biochemical response, which could help to assess the response to ARTA.

BACKGROUND: According to the National Comprehensive Cancer Network Guidelines, 18F-fluciclovine PET/CT is considered appropriate after negative standard of care (SOC) imaging.
OBJECTIVE: To prospectively compare 18F-fluciclovine to SOC imaging, investigate whether it should be done when SOC imaging is (+), and evaluate its detection rate in patients receiving androgen deprivation therapy.
METHODS: We recruited 57 prostate cancer patients with biochemical recurrence with 18F-fluciclovine PET/CT and SOC imaging within 30 days. Prostate-specific antigen (PSA) level, Gleason score (GS), history of radical prostatectomy (RP), radiation therapy (RT) or hormone therapy (HT) were reviewed.
RESULTS: The 57 patients had a median PSA of 2.6 and average GS of 7.4; 27 (47.4%) had RP, 28 (49.1%) had RT, 1 (1.75%) had HT and 1 (1.75%) observation only. 18F-fluciclovine identified disease recurrence in 45/57 patients (78.9%), including oligometastasis in 18/45 (40%). SOC imaging identified recurrent disease in 12/57 patients (21.1%) while 18F-fluciclvoine identified additional sites of disease in 11/12 (91.7%). The (+) 18F-fluciclovine studies had a median PSA 2.6 ng/ml compared to 6.0 ng/ml in the (+) SOC studies.
CONCLUSIONS: 18F-fluciclovine was superior to SOC imaging for lesion detection, identification of oligometastasis and identification of additional sites of disease.

Fatty acid binding protein 5 (FABP5) is a highly promising target for the development of analgesics as its inhibition is devoid of CB1R-dependent side-effects. The design and discovery of highly potent and FABP5-selective truxillic acid (TA) monoesters (TAMEs) is the primary aim of the present study. On the basis of molecular docking analysis, ca. 2,000 TAMEs were designed and screened in silico, to funnel down to 55 new TAMEs, which were synthesized and assayed for their affinity (Ki) to FABP5, 3 and 7. The SAR study revealed that the introduction of H-bond acceptors to the far end of the 1,1\'-biphenyl-3-yl and 1,1\'-biphenyl-2-yl ester moieties improved the affinity of α-TAMEs to FABP5. Compound γ-3 is the first γ-TAME, demonstrating a high affinity to FABP5 and competing with α-TAMEs. We identified the best 20 TAMEs based on the FABP5/3 selectivity index. The clear front runner is α-16, bearing a 2‑indanyl ester moiety. In sharp contrast, no ε-TAMEs made the top 20 in this list. However, α-19 and ε-202, have been identified as potent FABP3-selective inhibitors for applications related to their possible use in the protection of cardiac myocytes and the reduction of α-synuclein accumulation in Parkinson\'s disease. Among the best 20 TAMEs selected based on the affinity to FABP7, 13 out of 20 TAMEs were found to be FABP7-selective, with α-21 as the most selective. This study identified several TAMEs as FABP7-selective inhibitors, which would have potentially beneficial therapeutic effects in diseases such as Down\'s syndrome, schizophrenia, breast cancer, and astrocytoma. We successfully introduced the α-TA monosilyl ester (TAMSE)-mediated protocol to dramatically improve the overall yields of α-TAMEs. α-TAMSEs with TBDPS as the silyl group is isolated in good yields and unreacted α-TA/ α-MeO-TA, as well as disilyl esters (α-TADSEs) are fully recycled. Molecular docking analysis provided rational explanations for the observed binding affinity and selectivity of the FABP3, 5 and 7 inhibitors, including their α, γ and ε isomers, in this study.

Topical immunotherapy is widely used in the treatment of alopecia areata (AA). Alopecia areata incognita (AAI) is a relatively common disorder, predominantly affecting females, characterized by widespread hair thinning in the absence of typical alopecic patches. AAI can have a chronic relapsing course and in some cases can be resistant to current standard treatments. Topical immunotherapy has been used in the management of AA with encouraging results, but to date there are no literature studies reporting the efficacy of topical immunotherapy with squaric acid dibutylester (SADBE) in AAI. The aim of our study is to evaluate the efficacy and tolerance of topical immunotherapy with SADBE in AAI not responding to conventional steroid therapy. A total of 12 patients were enrolled in our Hair Disease Outpatient Service, with a proved histological diagnosis of AAI, and resistant to classical steroid therapy. Each patient underwent global photography, pull test, and trichoscopy at beginning and during the follow-ups. The efficacy of topical immunotherapy with SADBE was assessed by evaluating the changes of clinical and trichoscopic signs. Complete regrowth was achieved in 66.7% of cases (8/12), three patients remained unchanged on clinical evaluation but showed subclinical improvement on trichoscopy, whereas one patient progressed and worsened both on clinical and trichoscopic examination. All patients reported scalp diffuse mild erythema and itching the day after the application of SADBE, which were well tolerated. Three patients developed reactive cervical lymphoadenomegaly. No other side effects were observed. Topical immunotherapy with SADBE is widely used in the management of patchy AA and can be considered an effective alternative in resistant AAI, providing visible clinical and trichoscopic improvement in the majority of cases. Further studies are warranted to confirm and validate our findings.

This work outlines a synthetic route that can be used to access chiral cyclobutane keto acids with two stereocenters in five steps from the inexpensive terpene myrtenal. Furthermore, the developed route includes an 8-aminoquinoline-directed C(sp2)-H arylation as one of its key steps, which allows a wide range of aryl and heteroaryl groups to be incorporated into the bicyclic myrtenal scaffold prior to the ozonolysis-based ring-opening step that furnishes the target cyclobutane keto acids. This synthetic route is expected to find many applications connected to the synthesis of natural product-like compounds and small molecule libraries.

Cisplatin-based induction chemotherapy plus concurrent chemoradiotherapy in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma has been recommended in the National Comprehensive Cancer Network Guidelines. However, cisplatin is associated with poor patient compliance and has notable side-effects. Lobaplatin, a third-generation platinum drug, has shown promising antitumour activity against several malignancies with less toxicity. In this study, we aimed to evaluate the efficacy of lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy over a cisplatin-based regimen in patients with locoregional, advanced nasopharyngeal carcinoma.
In this open-label, non-inferiority, randomised, controlled, phase 3 trial done at five hospitals in China, patients aged 18-60 years with previously untreated, non-keratinising stage III-IVB nasopharyngeal carcinoma; Karnofsky performance-status score of at least 70; and adequate haematological, renal, and hepatic function were randomly assigned (1:1) to receive intravenously either lobaplatin-based (lobaplatin 30 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) or cisplatin-based (cisplatin 100 mg/m2 on days 1 and 22, and fluorouracil 800 mg/m2 on days 1-5 and 22-26 for two cycles) induction chemotherapy, followed by concurrent lobaplatin-based (two cycles of intravenous lobaplatin 30 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) or cisplatin-based (two cycles of intravenous cisplatin 100 mg/m2 every 3 weeks plus intensity-modulated radiotherapy) chemoradiotherapy. Total radiation doses of 68-70 Gy (for the sum of the volumes of the primary tumour and enlarged retropharyngeal nodes), 62-68 Gy (for the volume of clinically involved gross cervical lymph nodes), 60 Gy (for the high-risk target volume), and 54 Gy (for the low-risk target volume), were administered in 30-32 fractions, 5 days per week. Randomisation was done centrally at the clinical trial centre of Sun Yat-sen University Cancer Centre by means of computer-generated random number allocation with a block design (block size of four) stratified according to disease stage and treatment centre. Treatment assignment was known to both clinicians and patients. The primary endpoint was 5-year progression-free survival, analysed in both the intention-to-treat and per-protocol populations. If the upper limit of the 95% CI for the difference in 5-year progression-free survival between the lobaplatin-based and cisplatin-based groups did not exceed 10%, non-inferiority was met. Adverse events were analysed in all patients who received at least one cycle of induction chemotherapy. This trial is registered with the Chinese Clinical Trial Registry, ChiCTR-TRC-13003285 and is closed.
From June 7, 2013, to June 16, 2015, 515 patients were assessed for eligibility and 502 patients were enrolled: 252 were randomly assigned to the lobaplatin-based group and 250 to the cisplatin-based group. After a median follow-up of 75·3 months (IQR 69·9-81·1) in the intention-to-treat population, 5-year progression-free survival was 75·0% (95% CI 69·7-80·3) in the lobaplatin-based group and 75·5% (70·0 to 81·0) in the cisplatin-based group (hazard ratio [HR] 0·98, 95% CI 0·69-1·39; log-rank p=0·92), with a difference of 0·5% (95% CI -7·1 to 8·1; pnon-inferiority=0·0070). In the per-protocol population, the 5-year progression-free survival was 74·8% (95% CI 69·3 to 80·3) in the lobaplatin-based group and 76·4% (70·9 to 81·9) in the cisplatin-based group (HR 1·04, 95% CI 0·73 to 1·49; log-rank p=0·83), with a difference of 1·6% (-6·1 to 9·3; pnon-inferiority=0·016). 63 (25%) of 252 patients in the lobaplatin-based group and 63 (25%) of 250 patients in the cisplatin-based group had a progression-free survival event in the intention-to-treat population; 62 (25%) of 246 patients in the lobaplatin-based group and 58 (25%) of 237 patients in the cisplatin-based group had a progression-free survival event in the per-protocol population. The most common grade 3-4 adverse events were mucositis (102 [41%] of 252 in the lobaplatin-based group vs 99 [40%] of 249 in the cisplatin-based group), leucopenia (39 [16%] vs 56 [23%]), and neutropenia (25 [10%] vs 59 [24%]). No treatment-related deaths were reported.
Lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy resulted in non-inferior survival and fewer toxic effects than cisplatin-based therapy. The results of our trial indicate that lobaplatin-based induction chemotherapy plus concurrent chemoradiotherapy might be a promising alternative regimen to cisplatin-based treatment in patients with locoregional, advanced nasopharyngeal carcinoma.
National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University.
For the Chinese translation of the abstract see Supplementary Materials section.

Flavinium salts are frequently used in organocatalysis but their application in photoredox catalysis has not been systematically investigated to date. We synthesized a series of 5-ethyl-1,3-dimethylalloxazinium salts with different substituents in the positions 7 and 8 and investigated their application in light-dependent oxidative cycloelimination of cyclobutanes. Detailed mechanistic investigations with a coumarin dimer as a model substrate reveal that the reaction preferentially occurs via the triplet-born radical pair after electron transfer from the substrate to the triplet state of an alloxazinium salt. The very photostable 7,8-dimethoxy derivative is a superior catalyst with a sufficiently high oxidation power (E*=2.26 V) allowing the conversion of various cyclobutanes (with Eox up to 2.05 V) in high yields. Even compounds such as all-trans dimethyl 3,4-bis(4-methoxyphenyl)cyclobutane-1,2-dicarboxylate can be converted, whose opening requires a high activation energy due to a missing pre-activation caused by bulky adjacent substituents in cis-position.

Squaraine dyes are potential photosensitizers in photodynamic therapy (PDT) due to their ability to release reactive oxygen species (ROS) and cause DNA damage. For this reason, the evaluation and determination of the type of interaction between squaraines and DNA is of the utmost importance. In this study different spectroscopic techniques such as UV-Vis and fluorescence spectroscopies were used to investigate the type of interaction that occurs between two photosensitizers (halogenated squaraines, i.e. Br-C4 and I-C4) and calf thymus DNA (ctDNA). Squaraines were found to bind ctDNA externally following a minor groove binding as they were able to replace Hoechst (a classic groove binder) from the groove of DNA. This binding mode was further supported by iodide quenching studies, ionic strength assay and Florescence Resonance Energy Transfer. Moreover, association (KA) and dissociation (KD) constants were obtained and compared with constants of well-known groove binders.