N-acyl Sulfonamide Research Articles

Synthesis and evaluation of aromatic BDSF bioisosteres on biofilm formation and colistin sensitivity in pathogenic bacteria

The diffusible signal factor family (DSF) of molecules play an important role in regulating intercellular communication, or quorum sensing, in several disease-causing bacteria. These messenger molecules, which are comprised of cis-unsaturated fatty acids, are involved in the regulation of biofilm formation, antibiotic tolerance, virulence and the control of bacterial resistance. We have previously demonstrated how olefinic N-acyl sulfonamide bioisosteric analogues of diffusible signal factor can reduce biofilm formation or enhance antibiotic sensitivity in a number of bacterial strains. This work describes the design and synthesis of a second generation of aromatic N-acyl sulfonamide bioisosteres. The impact of these compounds on biofilm production in Acinetobacter baumannii, Escherichia coli, Burkholderia multivorans, Burkholderia cepacia, Burkholderia cenocepacia, Pseudomonas aeruginosa and Stenotrophomonas maltophilia is evaluated, in addition to their effects on antibiotic tolerance. The ability of these molecules to increase survival rates on co-administration with colistin is also investigated using the Galleria infection model.

Cobalt-Catalyzed Aerobic Aminocyclization of Unsaturated Amides for the Synthesis of Functionalized γ- and δ-Lactams.

We report the cobalt-catalyzed aminocyclization of unsaturated N-acyl sulfonamides in the presence of oxygen to provide γ- and δ-lactam aldehydes. Use of an optically active cobalt catalyst resulted in the formation of enantiomerically enriched γ-and δ-lactam alcohols. The γ-lactam aldehydes and alcohols obtained were elaborated into useful building blocks.

Synthesis of Aliphatic Nitriles via Desulfonylative Smiles Rearrangement

AbstractHerein, we demonstrate the synthesis of aliphatic nitriles from N-acyl (2-nitrophenyl)sulfonamides via a desulfonylative Smiles rearrangement. The developed reaction routes provide a variety of aliphatic nitriles containing primary, secondary, and tertiary carbon centers in good-to-excellent yields. Our method requires the use of the easy-to-handle reagent potassium acetate and solvent 1,3-dimethyl-2-imidazolidinone, and it does not rely on toxic metal cyanides or transition metals. The process is suitable for large-scale reaction and for one-pot syntheses starting from an acyl chloride or a carboxylic acid.

A dose-escalation and expansion study of the safety and pharmacokinetics of XB002 in subjects with inoperable locally advanced or metastatic solid tumors (301)

<b>Objectives:</b> Cervical cancer and epithelial ovarian cancer (EOC) are two of the most prevalent gynecologic cancers associated with high mortality. Despite recent advancements in therapy, there is an unmet need for novel treatments to improve survival outcomes. XB002 is an antibody-drug conjugate (ADC) that targets tissue factor (TF). TF is a protein overexpressed in many solid tumors, including gynecologic cancers, and is associated with disease progression and poor prognosis. XB002 is a human mAb (25A3) directed against TF conjugated to a novel cytotoxic agent (payload) N-acyl sulfonamide auristatin, ZD02044. XB002 has been designed to improve the therapeutic potential of ADCs targeting TF as a new therapeutic strategy in cancers. XB002 has demonstrated activity in several solid tumor xenograft models. The objective of this ongoing first-in-human study is to evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity (anti-drug antibodies [ADA]), and preliminary antitumor activity of XB002 in patients with advanced solid tumors with limited treatment options. Presented here are the trial design and details of the cervical and EOC cohorts. <b>Methods:</b> In this phase 1, non-randomized, open-label, multicenter, dose-escalation, and dose-expansion study (NCT04925284), patients with advanced solid tumors will receive XB002 IV every three weeks at a starting dose of 0.16 mg/kg. In the dose-escalation stage, an i3+3 study design will be used to identify the maximum tolerated dose (MTD)/recommended dose (RD) and/or the maximum allowed dose of XB002. Dose level decisions will be made by the Cohort Review Committee after review of all available safety and PK data. In the cohort-expansion phase, the MTD/RD will be further evaluated for safety and preliminary efficacy in multiple tumor-specific expansion cohorts that will be enrolled using a Simon's 2-stage design. Patients will be treated until radiographic progression per RECIST v1.1 or unacceptable toxicity. Patients in the cervical and EOC expansion cohorts must have received ≤2 (cervical) or ≤3 (EOC) lines of prior systemic anticancer therapy for locally advanced or metastatic disease. Patients must have received prior platinum-containing therapy in both cohorts, and patients must have platinum-resistant disease in the EOC cohort. The primary endpoint of the cohort-expansion stage will be objective response rate (ORR) per RECIST v1.1 assessed by the investigator. Other endpoints will include duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 assessed by the investigator, and overall survival; ORR, DOR, and PFS may also be assessed by a blinded independent radiology committee in select expansion cohorts. The effects of XB002 on tumor and blood biomarkers, including TF expression, will be assessed in exploratory analyses. For patients with EOC, blood samples for CA125 assessment will be collected at screening and throughout treatment in both stages of the study.

Cobalt-Catalyzed Cyclization of Unsaturated N-Acyl Sulfonamides: a Diverted Mukaiyama Hydration Reaction.

The cycloisomerization of β-, γ-, and δ-unsaturated N-acyl sulfonamides to N-sulfonyl lactams and imidates is reported. This transformation is effected in the presence of a CoIII(salen) catalyst using t-BuOOH or air as the oxidant. The method shows good functional group tolerance (alkyl, aryl, heteroaryl, ether, N-Boc) and furnishes an underexplored class of cyclic building blocks. The strong solvent dependence of the transformation is investigated, and the synthetic versatility of the N-sulfonyl imidate product class is highlighted.

Energy-entropy prediction of octanol\u2013water logP of SAMPL7 N-acyl sulfonamide bioisosters

Partition coefficients quantify a molecule’s distribution between two immiscible liquid phases. While there are many methods to compute them, there is not yet a method based on the free energy of each system in terms of energy and entropy, where entropy depends on the probability distribution of all quantum states of the system. Here we test a method in this class called Energy Entropy Multiscale Cell Correlation (EE-MCC) for the calculation of octanol–water logP values for 22 N-acyl sulfonamides in the SAMPL7 Physical Properties Challenge (Statistical Assessment of the Modelling of Proteins and Ligands). EE-MCC logP values have a mean error of 1.8 logP units versus experiment and a standard error of the mean of 1.0 logP units for three separate calculations. These errors are primarily due to getting sufficiently converged energies to give accurate differences of large numbers, particularly for the large-molecule solvent octanol. However, this is also an issue for entropy, and approximations in the force field and MCC theory also contribute to the error. Unique to MCC is that it explains the entropy contributions over all the degrees of freedom of all molecules in the system. A gain in orientational entropy of water is the main favourable entropic contribution, supported by small gains in solute vibrational and orientational entropy but offset by unfavourable changes in the orientational entropy of octanol, the vibrational entropy of both solvents, and the positional and conformational entropy of the solute.

Synthetic routes to treprostinil N-acyl methylsulfonamide

The synthesis of the prodrug candidate, treprostinil N-acyl methylsulfonamide 5 was accomplished from treprostinil 2 utilising protecting group strategies. A more direct synthesis for the prodrug was also achieved using a treprostinil triol precursor 12 and bromoacetyl acylmethylsulfonamide 14. The overall yield of treprostinil N-acyl sulfonamide 5 directly from the triol precursor 12 is similar to the protecting group strategies because deprotonation of the acidic proton in the bromoacetyl acylmethylsulfonamide 14 reduces electrophilicity. However, the more direct route using the treprostinil triol precursor holds greater promise as a strategy to prepare a wide range of treprostinil prodrug candidates. Treprostinil N-acyl methylsulfonamide prodrug 5 exhibited a 30-fold decrease in the potency at the human prostacyclin (IP) receptor compared to treprostinil 2 in an in vitro cyclic AMP assay.

Abstract P6-17-13: ZW49, a HER2 targeted biparatopic antibody drug conjugate for the treatment of HER2 expressing cancers

Abstract Background: HER2-targeted therapies have transformed the treatment of patients with HER2-expressing breast and gastric cancers. Despite this, there remains a need for new treatments that are well tolerated and effective not only for cancers with high HER2 expression levels but also those with lower levels of expression. ZW49 is an antibody drug conjugate (ADC) that combines a novel auristatin payload (potent anti-cancer agent) with the unique mechanisms of action of the anti-HER2 biparatopic antibody, ZW25, which binds to the same domains as trastuzumab and pertuzumab. In preclinical studies in cancer cell lines with low to high levels of HER2 expression, ZW25 is associated with increased binding and internalization compared to trastuzumab, while the novel N-acyl sulfonamide auristatin payload has demonstrated increased in vivo tolerability compared to other microtubule inhibitors. ZW49 therefore has the potential to address unmet medical need across a range of HER2-expressing cancers. Methods: Multiple in vitro and in vivo experiments were performed to characterize ZW49 as a potential therapeutic candidate. Internalization and cell growth inhibition of ZW49 were evaluated in HER2-expressing cell lines. Anti-tumor activity was assessed in patient-derived xenograft (PDX) tumor models of HER2 low and high expressing breast cancers. Tolerability was assessed in a 6-week repeat-dose non-GLP toxicology study in non-human primates (NHP) with intravenous administration of ZW49 at either 9 mg/kg or 12 mg/kg once every two weeks. Results: In vitro, ZW49 was more rapidly internalized into HER2-expressing cells compared to a monospecific trastuzumab-ADC. ZW49 also displayed potent in vitro cell growth inhibition in several breast cancer cell lines with a range of HER2 expression. This activity was confirmed in multiple in vivo PDX models, including a HER2 IHC 3+ HBCx-13b xenograft where two doses of ZW49 at 3 mg/kg or higher generated tumor regressions, and a HER2 IHC 1+ ST-910 xenograft where a single dose of ZW49 at 6 mg/kg or higher generated regressions. In both models, regressions occurred at exposures that were well tolerated in NHP. In a repeat dose pilot non-GLP study the highest dose tested (12 mg/kg) was considered to be the no observed adverse effect level (NOAEL) and a GLP repeat-dose toxicology study was ongoing at the time of abstract submission. Conclusions: ZW49 is a novel biparatopic HER2-targeted ADC that demonstrated anti-tumor activity in low and high HER2-expressing breast cancer cell lines and PDX models. Notably, tumor regressions were observed at exposure levels that were well tolerated in NHP. These results support the potential of ZW49 as a novel therapeutic agent that may help address unmet medical need in patients with high and low HER2-expressing cancers. Citation Format: Hamblett KJ, Barnscher SD, Davies RH, Hammond PW, Hernandez A, Wickman GR, Fung VK, Ding T, Garnett G, Galey AS, Zwierzchowski P, Clavette BC, Winters GC, Rich JR, Rowse GJ, Babcook JS, Hausman D. ZW49, a HER2 targeted biparatopic antibody drug conjugate for the treatment of HER2 expressing cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-13.

Efficient N-acylation of sulfonamides using cesium salt of Wells–Dawson heteropolyacid as catalyst: Synthesis of new N-acyl sulfonamides and cyclic imides

N-acylation of substituted sulfonamides with different anhydrides in the presence of Cesium salt of Wells–Dawson heteropolyacid (Cs5HP2W18O62) as an efficient and reusable catalyst was investigated for the first time. Cs5HP2W18O62 was used with a catalytic amount in water as a green solvent. At room temperature, a series of N-acylsulfonamides were synthesized, while under refluxing conditions, new cyclic imides containing sulfonyl group were obtained. Atom-economy, high yields, easy work-up, as well as simple catalyst recovery and reusability are the key features of this procedure.

Abstract 3912: Towards development of next-generation biparatopic ADCs using a novel linker-toxin with expanded therapeutic window

Abstract Antibody drug conjugate (ADC) therapies such as Kadcyla® and Adcetris® have significantly improved outcomes for patients. Despite these early advances, many ADCs have failed due to tolerability and efficacy concerns; therefore, there is a need to develop ADCs with a greater therapeutic window. We have previously reported the increased tolerability of a novel N-acyl sulfonamide auristatin payload conjugated to trastuzumab via a protease cleavable linker. In non-human primates (NHPs), the HNSTD for this ADC was 18 mg/kg compared to 3 mg/kg for the MMAE conjugate control. Separately, we have also reported that a biparatopic antibody targeting a tumor associated antigen (e.g. anti-HER2 bispecific antibody ZW25) can lead to enhanced receptor clustering and improved internalization, thereby increasing the efficiency of payload delivery. Our aim is to develop a series of novel biparatopic ADCs with expanded therapeutic windows against multiple targets. Here we present the proof-of-concept in vitro and in vivo characterization of benchmark ADCs against 3 different targets with improved tolerability and equivalent efficacy. Benchmark antibodies against 3 known clinical targets were conjugated to our N-acyl sulfonamide auristatin (mAb-ADCs) or to MMAE or DM4 controls (mAb-control ADCs) via cleavable linkers and were assessed for in vitro binding affinity and cytotoxicity. The therapeutic windows of mAb-ADCs and mAb-control ADCs were compared by assessing efficacy in mouse xenograft models and tolerability and pharmacokinetics in NHPs. mAb-ADCs had similar binding affinities to recombinant targets and/or to cancer cells expressing low to high levels of target antigen compared to the mAb-control ADCs. mAb-ADCs demonstrated similar in vitro cytotoxicity compared to mAb-control ADCs and this was recapitulated in vivo with similar tumor growth inhibition in mouse xenograft models. In a NHP tolerability/PK study, mAb-ADCs for all 3 targets were tolerated at doses up to 18 mg/kg (single dose IV infusion) compared to the mAb-control ADCs that showed severe to life-threatening neutropenia at lower doses. The increase in maximum tolerated dose for the mAb-ADCs over the mAb-control ADCs, together with comparable efficacy across 3 different targets, demonstrates the broad applicability of the novel N-acyl sulfonamide auristatin payload to expand the therapeutic window. This strategy, together with ongoing efforts to identify synergistic antibody paratopes that more efficiently deliver payload, could lead to next-generation biparatopic ADCs with improved activity. Citation Format: Rupert H. Davies, Stuart D. Barnscher, Peter W. Chan, Laurence Madera, Jamie R. Rich, Marylou Vallejo, Grant R. Wickman, Kevin Yin, Vincent Fung, Kevin J. Hamblett, Patrick G. Kaminker, John S. Babcook. Towards development of next-generation biparatopic ADCs using a novel linker-toxin with expanded therapeutic window [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3912.

Abstract 3914: ZW49, a HER2-targeted biparatopic antibody-drug conjugate for the treatment of HER2-expressing cancers

Abstract Therapies targeting HER2 have transformed the treatment of patients with HER2-expressing breast and gastric cancers. Unfortunately, many patients recur following HER2-targeted treatments and new therapies are needed. Multiple antibody-drug conjugate (ADC) technologies are being explored in this setting, some of which utilize the anti-HER2 antibody trastuzumab. Here we present the preclinical characterization of a new anti-HER2 biparatopic ADC, ZW49, which is generated from the conjugation of a novel N-acyl sulfonamide auristatin payload to the inter-chain disulfide bond cysteines of the bispecific anti-HER2 IgG1 antibody ZW25, via a protease cleavable linker. A series of in vitro and in vivo experiments were performed to characterize ZW49 as a potential therapeutic candidate. In cellular binding assays, it was confirmed that the payload conjugation to ZW25 did not affect the antibody's binding to HER2-expressing cells. ZW49 displayed potent in vitro cytotoxicity in multiple cancer cell lines expressing HER2 and was efficacious in multiple patient-derived xenograft (PDX) models. In mice bearing the HBCx-13b HER2 3+ PDX, two doses of ZW49 administered two weeks apart generated tumor regressions. Furthermore, preliminary results from PDX models with lower levels of HER2 expression treated with ZW49 also generated regressions. In nonhuman primates ZW49 administered intravenously every two weeks for three doses was well tolerated. Based on these findings, we are proceeding with further development of ZW49 as a therapeutic candidate in HER2-expressing cancers. Citation Format: Kevin J. Hamblett, Phil W. Hammond, Stuart D. Barnscher, Vincent K. Fung, Rupert H. Davies, Grant R. Wickman, Andrea Hernandez, Tong Ding, Adam S. Galey, Geoffrey C. Winters, Jamie R. Rich, John S. Babcook. ZW49, a HER2-targeted biparatopic antibody-drug conjugate for the treatment of HER2-expressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3914.

Abstract 61: Zymelink drug conjugate platform: redefining the therapeutic window for ADCs

Abstract Antibody drug conjugates (ADCs) combine the specificity of monoclonal antibodies with potent antineoplastic small molecules, and promise efficacy without the systemic toxicity of chemotherapy. Despite this tremendous potential, most clinical ADCs have failed to provide sufficient therapeutic benefit before the onset of off-target dose-limiting platform toxicities. Here we report the development of proprietary protease cleavable N-acyl sulfonamide linked hemiasterlin and auristatin payloads, Zymelink, that allow the generation of an efficacious ADC platform with improved tolerability. Both Zymelink drug-linkers were conjugated via maleimides to endogenous cysteines. As Zymelink drug-linkers are more polar than maleimide valine citrulline monomethyl auristatin E drug-linker, the resulting ADCs can be produced with potential advantages in PK, efficacy and safety. The resulting ADCs exhibit potent in vitro cytotoxicity. A trastuzumab-based ADC prepared with Zymelink drug-linker and demonstrated at least equivalent efficacy compared to a trastuzumab-based ADC prepared with MMAE, promoting durable complete regressions in a patient-derived xenograft model. Zymelink hemiasterlin and auristatin ADCs were tolerated at 5-6 fold higher doses compared to a MMAE ADC in cynomolgus monkeys. The maximum tolerated dose of the MMAE ADC was just 3 mg/kg based on severe neutropenia. Zymelink hemiasterlin ADC was tolerated at 15 mg/kg with no evidence of neutropenia or elevations in transaminases. Zymelink auristatin ADC was tolerated at 18 mg/kg based on increased levels of transaminases at 24 mg/kg. Moreover, Zymelink ADCs exhibited greater serum exposure at equivalent doses. These results suggest Zymelink ADCs have a greatly expanded therapeutic window compared to MMAE conjugates. Citation Format: Stuart Barnscher, John Babcook, Jamie Rich, Geoff Winters, Graham Garnett, Andrea Hernandez, Vincent Fung, Kevin Yin, Kevin Hamblett, Rupert Davies. Zymelink drug conjugate platform: redefining the therapeutic window for ADCs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 61. doi:10.1158/1538-7445.AM2017-61

A practical method for regiocontrolled one-carbon ring contraction

A practical and efficient method for the perfluorobutanesulfonyl azide-mediated one-carbon ring contraction of cyclic enoxysilanes is described. High-yielding procedures for the elaboration of the resulting N-acyl sulfonamide products are reported.

A novel and efficient method for N-acylation of sulfonamides and carbamates: Their biological evaluation towards anti Malassezia activity

BackgroundThe N-acylation of sulfonamides and carbamates with acid anhydrides in the presence of Lewis catalysis has been described. The N-acylation of various sulfonamides and carbamates with carboxylic acid anhydrides were effectively promoted by catalytic amount of CeCl3 under solvent-free conditions to produce the corresponding N-acyl products in good to excellent yields. The synthesized compounds were tested for their antifungal activity. MethodsTo a mixture of sulfonamide and anhydride, and anhydrous CeCl3 was added and the reaction was stirred for the given time. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with water and brine solution. The combined organic layers were dried over Na2SO4 and evaporated in vacuum. The crude compound was purified by column chromatography to afford the corresponding N-acylated product. ResultsSynthesized compounds were screened for their antifungal activity against two virulent organisms Malassezia furfur and Malassezia pachydermatis. The compounds were tested in different concentrations ranging from 200 uM to 1 uM and taking their growth observations at OD 600 nm at different time intervals. The growth in the treated wells was compared with the growth in the untreated wells. Ketoconazole was used as control, among the compounds screened 2a, 2i and 4a showed activity than the standard antifungal drug i.e. Ketoconazole. ConclusionSynthesized compounds were evaluated for their antifungal activity and three compounds 2a, 2i, and 4a showed very good activity against both the organisms, for the first time N-acyl sulfonamides and carbamates classes were evaluated as potential anti-Malassezia agents.

ChemInform Abstract: Sulfo‐Click Reaction via in situ Generated Thioacids and Its Application in Kinetic Target‐Guided Synthesis.

AbstractA one‐pot variant of the sulfo‐click reaction in presented, in which protected thioesters (I) and (IV) are rapidly deprotected and further subjected to the reaction with sulfonylazides (II) and (V) to afford N‐acyl sulfonamides (III) and (VI), respectively.

Sulfo-click reaction via in situ generated thioacids and its application in kinetic target-guided synthesis

Herein, we describe a practical, one-pot variant of the sulfo-click reaction, in which 9-fluorenylmethyl-protected thioesters are rapidly deprotected and reacted further with sulfonylazides to give N-acyl sulfonamides.

A novel and efficient solvent-free and heterogeneous method for the synthesis of primary, secondary and bis- N-acylsulfonamides using metal hydrogen sulfate catalysts

Some metal hydrogen sulfates were used as acid catalysts in the N-acylation of different sulfonamides using carboxylic acid chlorides and anhydrides as acylating agents under both heterogeneous and solvent-free conditions. Al(HSO 4) 3 and Zr(HSO 4) 4 were found to have the highest activity and catalyze the reactions efficiently to furnish the primary N-acyl sulfonamides (RCONHSO 2R′), secondary N-acylsulfonamides (RCONR″SO 2R′) and bis- N-acylsulfonamnides [RCO(SO 2R′)N-R″-N(SO 2R′)COR] in good to high yield. The mild reaction conditions, inexpensive and low toxicity of catalysts and easy work-up procedure make this method attractive.

A new and efficient method for the facile synthesis of N-acyl sulfonamides under Lewis acid catalysis

The N-acylation of sulfonamides with carboxylic acid anhydrides in the presence of Lewis acids is described. Several Lewis acids such as BF 3·Et 2O, ZnCl 2, MoCl 5, TiCl 4, B(C 6F 5) 3, Sc(OTf) 3 and I 2 were found to catalyze the reaction efficiently to furnish the N-acylated products in good yields under solvent-free conditions. The reactions of various sulfonamides were studied with different carboxylic acid anhydrides including the less reactive benzoic and pivalic anhydrides, in the presence of 3 mol % ZnCl 2 as the catalyst. Carboxylic acids were also successfully used as acylating agents via the mixed anhydride method.

Resin-Bound Sulfonyl Azides: Efficient Loading and Activation Strategy for the Preparation of the N-Acyl Sulfonamide Linker

This paper describes an optimized protocol for the efficient loading of resin-bound aminoethane sulfonyl azides by either Boc- or Fmoc-protected amino thioacids. The resulting N-acyl sulfonamide is a convenient linker for use in Boc- or Fmoc-based solid-phase peptide synthesis. Activation of the N-acyl sulfonamide via a microwave-assisted alkylation procedure and subsequent treatment with functionalized nucleophiles yields C-terminally modified peptides that can be applied in chemoselective (bio)conjugation or ligation reactions.

Thio Acid/Azide Amidation: An Improved Route to N‐Acyl Sulfonamides.

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