Christopher McGuigan

The androgen receptor (AR) is a pivotal target for the treatment of prostate cancer (PC) even when the disease progresses toward androgen-independent or castration-resistant forms. In this study, a series of 15 bicalutamide analogues (sulfide, deshydroxy, sulfone, and O-acetylated) were prepared and their antiproliferative activity evaluated against four different human prostate cancer cell lines (22Rv1, DU-145, LNCaP, and VCap). Bicalutamide and enzalutamide were used as positive controls. Seven of these compounds displayed remarkable enhancement in anticancer activity across the four PC cell lines. The deshydroxy analogue (16) was the most active compound with IC₅₀ = 6.59–10.86 µM. Molecular modeling offers a plausible explanation of the higher activity of the sulfide analogues compared to their sulfone counterparts.

Following a drug repurposing approach, we aimed to investigate and compare the antibacterial and antibiofilm activities of different classes of phosphate prodrugs (HepDirect, cycloSal, SATE and mix SATE) of antiviral and anticancer FDA-approved nucleoside drugs [zidovudine (AZT), floxouridine (FUDR) and gemcitabine (GEM)] against a variety of pathogenic Gram-positive and -negative bacteria. Ten prodrugs were synthesized and screened for antibacterial activity against seven Gram-negative and two Gram-positive isolates fully susceptible to traditional antibiotics, alongside six Gram-negative and five Gram-positive isolates with resistance mechanisms. Their ability to prevent and eradicate biofilms of different bacterial pathogens in relation to planktonic growth inhibition was also evaluated, together with their effect on proliferation, viability and apoptosis of different eukaryotic cells. The prodrugs showed decreased antibacterial activity compared with the parent nucleosides. cycloSal-GEM-monophosphate (MP) prodrugs 20a and 20b were the most active agents against Gram-positive bacteria (Enterococcus faecalis and Staphylococcus aureus) and retained their activity against antibiotic-resistant isolates. cycloSal-FUDR-MP 21a partially retained good activity against the Gram-positive bacteria E. faecalis, Enterococcus faecium and S. aureus. Most of the prodrugs tested displayed very potent preventive antibiofilm specific activity, but not curative. In terms of cytotoxicity, AZT prodrugs did not affect apoptosis or cell viability at the highest concentration tested, and only weak effects on apoptosis and/or cell viability were observed for GEM and FUDR prodrugs. Among the different prodrug approaches, the cycloSal prodrugs appeared the most effective. In particular, cycloSal (17a) and mix SATE (26) AZT prodrugs combine the lowest cytotoxicity with high and broad antibacterial and antibiofilm activity against Gram-negative bacteria.

Phosphoramidate pro-nucleotides (ProTides) have revolutionized the field of anti-viral and anti-cancer nucleoside therapy, overcoming the major limitations of nucleoside therapies and achieving clinical and commercial success. Despite the translation of ProTide technology into the clinic, there remain unresolved in vivo pharmacokinetic and pharmacodynamic questions. Positron Emission Tomography (PET) imaging using [¹⁸F]-labelled model ProTides could directly address key mechanistic questions and predict response to ProTide therapy. Here we report the first radiochemical synthesis of [¹⁸F]ProTides as novel probes for PET imaging. As a proof of concept, two chemically distinct radiolabelled ProTides have been synthesized as models of 3′- and 2′-fluorinated ProTides following different radiosynthetic approaches. The 3′-[¹⁸F]FLT ProTide was obtained via a late stage [¹⁸F]fluorination in radiochemical yields (RCY) of 15–30% (n = 5, decay-corrected from end of bombardment (EoB)), with high radiochemical purities (97%) and molar activities of 56 GBq/μmol (total synthesis time of 130 min.). The 2′-[¹⁸F]FIAU ProTide was obtained via an early stage [¹⁸F]fluorination approach with an RCY of 1–5% (n = 7, decay-corrected from EoB), with high radiochemical purities (98%) and molar activities of 53 GBq/μmol (total synthesis time of 240 min).

5565 Background: Acelarin is a first-in-class nucleotide analogue utilising phosphoramidate chemistry to overcome the key gemcitabine resistance mechanisms and generate high intracellular levels of the active cytotoxic dFdCTP. In a Phase I, single agent, dose escalation study, Acelarin was well tolerated with impressive clinical activity. In a subset of 13 patients (pts) with ovarian cancer, Acelarin achieved a durable disease control rate, DCR intention-to-treat (ITT) 69%; on-treatment analyses (OTA) 90% and median PFS 8.3 months in evaluable pts. Therefore, we undertook a Phase Ib dose escalation study combining Acelarin with carboplatin in women with advanced ovarian cancer. Methods: Acelarin was administered as an injection on days 1 & 8 with carboplatin at AUC 4 or 5 on day 1, every 3 weeks for ≤ 6 cycles. Primary endpoint was RP2D; secondary endpoints included safety, ORR, PFS and PK/PD. Results: To date, 15 pts (mean age 65 yrs) with metastatic ovarian cancer, a median platinum free interval of 4 months and an average of 2.9 prior lines of chemotherapy, have been enrolled. Four dose cohorts of Acelarin (500; 625 and 750 mg/m²) with carboplatin (AUC4 or 5) have been studied. Nine pts completed 6 cycles of treatment and 3 pts remain on study. Strong early efficacy signals were achieved: 1 RECIST Complete Response (7%); 2 Partial Responses (13%) and 11 Stable Diseases (73%) resulting in a DCR ITT 93%; OTA 100%. Median PFS was 6.0 months (range 1.2 - 11.5) and 7 pts have ongoing disease control. PK showed that Acelarin was stable in the plasma (t_1/2 = 3.8 hrs). The combination regimen rapidly generated very high intracellular dFdCTP levels (C_max = 12.1 µM/mgTP/500mg/m² and T_max = 30 min) and significant levels were maintained for 24 hrs. The combination regimen was well tolerated. SAEs were reported in 4 pts: febrile neutropaenia (2); thrombocytopaenia (2); dyspnoea (1) and dizziness (1). Two DLTs were observed: grade 4 thrombocytopaenia at Acelarin 625mg/m² and 750mg/m² plus carboplatin AUC4. Conclusions: The combination of Acelarin with carboplatin was well tolerated and demonstrated remarkable clinical activity with durable disease control rate (ITT 93%; OTA 100%). Phase II studies in ovarian cancer are being planned. Clinical trial information: NCT02303912.

Gemcitabine is a nucleoside analogue commonly used in cancer therapy but with limited efficacy due to a high susceptibility to cancer cell resistance. The addition of a phosphoramidate motif to the gemcitabine can protect it against many of the key cancer resistance mechanisms. We have synthesized a series of gemcitabine phosphoramidate prodrugs and screened for cytostatic activity in a range of different tumor cell lines. Among the synthesized compounds, one in particular (NUC-1031, 6f) was shown to be potent in vitro. Importantly, compared with gemcitabine, 6f activation was significantly less dependent on deoxycytidine kinase and on nucleoside transporters, and it was resistant to cytidine deaminase-mediated degradation. Moreover, 6f showed a significant reduction in tumor volumes in vivo in pancreatic cancer xenografts. The ProTide 6f is now in clinical development with encouraging efficacy signals in a Phase I/II study, which strongly supports the ProTide approach to generate promising new anticancer agents.