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. Author manuscript; available in PMC: 2019 Dec 15.
Published in final edited form as: Bioorg Med Chem Lett. 2018 Oct 24;28(23-24):3652–3657. doi: 10.1016/j.bmcl.2018.10.036

Analogs of penfluridol as chemotherapeutic agents with reduced central nervous system activity☆

Md Ashraf-Uz-Zaman 1, Md Sanaullah Sajib 1, Luca Cucullo 1, Constantinos M Mikelis 1, Nadezhda A German 1,*
PMCID: PMC6438620  NIHMSID: NIHMS1007541  PMID: 30389290

Abstract

Several recent reports have highlighted the feasibility of the use of penfluridol, a well-known antipsychotic agent, as a chemotherapeutic agent. In vivo experiments have confirmed the cytotoxic activity of penfluridol in triple-negative breast cancer model, lung cancer model, and further studies have been proposed to assess its anticancer activity and viability for the treatment of glioblastomas. However, penfluridol anticancer activity was observed at a dosage significantly higher than that administered in antipsychotic therapy, thus raising the concern for the potential onset of CNS side effects in patients undergoing intensive pharmacological treatment. In this study, we evaluate the potential CNS toxicity of penfluridol side by side with a set of analogs.

Keywords: Penfluridol, Anticancer agent, Central nervous system, Repurposing, Toxicity, Optimization

Traditionally, de novo drug discovery for cancer treatment is invariably associated with high cost for preclinical and clinical studies which is estimated at approximately 1.042 billion dollars per drug1. Therefore, repurposing approved drugs to extend their therapeutic viability to other diseases (such as cancer treatment) is likely to afford the quickest and most cost-effective transition from bench to bedside2,3. At the same time, to avoid potential side toxicity issues, it is crucial to gather all available toxicological information associated with the use of a given drug4 and prevent scenarios similar to bevacizumab, cetuximab and others5, the USA Food and Drug Administration (FDA) developed guidance for a systemic approach to collect and report compound-associated toxicities6. This is especially important when the proposed dosage and/or frequency of administration of a repurposed drug are substantially different (higher) than those previously associated for its original therapeutic scope.

Among the many drugs being tested for their off-label activities, penfluridol, an oral antipsychotic agent7, was investigated for its anticancer properties8. Several groups have reported that this compound reduces cancer growth in vitro and in vivo9–15. Encouraging tumorkilling data and ability of this drug to cross the blood-brain barrier (BBB) prompt the idea of using this agent in the treatment of glioblastoma12,13 and cancers that have high rates of metastasis in the brain, including metastatic triple-negative breast cancer10 and lung cancers14. However, in vivo data also indicated that anticancer dosage should be considerably higher (estimated at 50 mg of daily dosing in human)10–12,15,16 than those used for the treatment of chronic schizophrenia and similar psychotic disorders (weekly oral dosing of 20 mg to 100 mg, 160 mg for resistant cases)17. Earlier, clinical data report neurological side effects attributed to the antipsychotic use of penfluridol, including epilepsy, fatigue, dyskinesias, Parkinsonism, akathisia, dystonia and depression, although the numbers are at the lower range18–20. Because penfluridol is capable of penetrating the BBB we estimated that the dosage required to produce chemotherapeutic activities10–12 would substantially increase the incidence of neurological side effects already associated with its use, thus impacting the sustainability and overall benefits associated with the treatment.

To assess these potential side-effects, we have evaluated the ability of penfluridol to inhibit major groups of G-coupled protein receptors (GPCRs) that are expressed in the brain21. Our data have confirmed that this compound has a multitarget CNS profile with the majority of Ki values being in the nanomolar range (see Table 1).

Table 1.

Inhibitory activity of penfluridol at selected CNS receptors.

5HT1A 5HT1D 5HT2A 5HT2B 5HT2C 5HT5a 5HT6 5HT7 D1 D2 D3 D4 D5
Inhibition, % 100 91.3 95.2 97.3 95.3 95.0 96.0 98.4 96.5 71.5 98.2 77.6 82.9
Ki, nM 356 3560 361 184 881 103 103 280 147 159 136 103 125
KOR MOR DOR H1 H2 NET SERT DAT Alpha 1D Alpha 2B Alpha 2C Beta 3
Inhibition, % 94.6 87.0 89.1 84.0 98.4 86.2 92.7 89.1 95.7 95.6 100 94.0
Ki, nM 103 867 1714 103 103 588 103 1714 602 401 445 515
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An initial literature analysis has shown that the available pharmacophore for CNS activity of penfluridol22,23 somewhat diverges from the one reported for its anticancer property24,25 (Fig. 1). Therefore, we have hypothesized that by leveraging the pharmacophores activities to promote its anticancer properties while reducing its GPCRs activities we can develop a more effective and safer chemotherapeutic penfluridol analog. Multiple modifications of the right – side motif containing the 4-substituted piperidine ring highlighted the importance of spatial orientation of the piperidine residue and hydroxy group for anticancer and antipsychotic activity22–25. It appears that this part of the molecule interacts with both targets via hydroxyl bonding and stabilizes the active conformation required for both types of biological activity. Hence, we have prepared analogs with the modifications in the linker motif and the left part of the original penfluridol structure. During the initial stage of our project, we have screened the obtained derivatives for their ability to inhibit selected GPCRs and to inhibit the growth of cancer cells in vitro, followed by evaluation of the top compound for its ability to cross the BBB in vivo. In addition, we have identified the dosing regimen that is required to achieve a therapeutic dose of selected compounds in mice.

Fig. 1.

Fig. 1.

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Structural requirements for antipsychotic and anticancer activities of penfluridol and its analogs23,24.

The proposed derivatives were prepared in good yields using a previously published procedure24,26–28 as depicted in Schemes 1 through 3 and in Schemes S1–S2 (supplemental material). In particular, the right moiety of all analogs was prepared by reacting a Grignard reagent with the N-BOC piperidone, followed by deprotection step in the presence of hydrochloric acid in ethanol24 (Scheme S1). As shown in Scheme S2 (supplemental material), the left part of compounds was constructed using selected benzene derivatives and the corresponding lactones to produce the intermediate 5 that was further utilized in preparing a key intermediate 7 (Scheme 1). This compound was coupled with a moiety 2 (Scheme S1, supplemental material) to obtain the final diphenyl butyl- or diphenyl pentylpipreridines 8 and 6. In Scheme 2, synthesis of analogs 11a and 11b started with the amination of aryl chloride using 1,1′-bis(diphenylphosphino)ferrocene (DPPH) as a catalyst.27 Next, the coupling of 9 with dibromo- or bromo-chloroalkane afforded intermediate 10 which was further reacted with 2 to afford compounds 11a and 11b in 10% and 24% overall yield respectively. Finally, in Scheme 3 monophenyl analog 13 was prepared in three steps following the published procedure26 to afford the desired product in 8% overall yield. All products were purified by flash chromatography and characterized using 1H and 13C NMR. The purity of all compounds was at or above 95% (supplemental material).

Scheme 1.

Scheme 1.

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Reagents and conditions: (a) Pd/C, H2, EtOH, r.t. (b) 2, Na2CO3, Kl, CH3CN, reflux.

Scheme 3.

Scheme 3.

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Reagents and conditions: (a) LiAlH4, THF, 0 °C to r.t.; (b) CBr4, Ph3P, DCM, 0 °C to r.t.; (c) 2, Na2CO3, KI, CH3CN, reflux.

Scheme 2.

Scheme 2.

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Reagents and conditions: (a) 1,1′-Ferrocenediyl-bis(diphenylphosphine), Pd(dppf)Cl2. CH2Cl2, KtBuO, anhydrous THF, 100 °C; (b) NaH, THF, 80 °C; (c) 2, Na2CO3, Kl, CH3CN, reflux.

To confirm that the proposed changes retain similar cytotoxic as penfluridol, analogs were evaluated in vitro using two cancer cell lines of both mouse and human origin: mouse-derived luciferin-expressing Lewis Lung Carcinoma (LLC luc) cell line and human triple-negative breast cancer cell line (MDA MB-231) using the 3-[4, 5-dimethylthiazol2-yl]-2, 5-dimethyltetrazolium bromide (MTT) colorimetric assay29. All experiments were performed in triplicates to ensure good reproducibility and penfluridol was used as a positive control. Data were obtained at 24 h, 48 h, and 72 h and IC50 values (μM) were calculated (supplementary materials). Among all derivatives tested, compounds 8a, 8c and 11a showed the best activity (IC50 3.5–7.1 μM), with little to no reduction when compared to penfluridol (IC50 4.3–5.1 μM). All three compounds have modifications in the spacer linker including elongation of the chain by one carbon (8a and 8c) or introduction of nitrogen atom (11a). An unsaturated linker with the elongated chain 6 (IC50 9.6–11.2 μM) caused a two-fold reduced cytotoxicity when compared to penfluridol. Interestingly, when two favorable features, such as elongated linker and N-containing linker, were combined, the activity has decreased (11b, IC50 8.2–9.2 μM). Next, modifications of the left motif, including unsubstituted phenyl moieties (8b) and monophenyl analog (13) were marked by the reduced activity, whereas introduction of methoxy group was tolerated (8c, IC50 6–7 μM). Overall, in vitro cytotoxicity data have shown that all designed analogs were active against selected cancer cell lines, supporting our hypothesis that these modifications will not alter significantly the anticancer activity of the original penfluridol molecule.

Next, we have investigated the effect of the proposed changes on the inhibition of selected G-protein coupled receptors (GPCRs). Receptor binding profile and Ki determinations were provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, where primary binding assay has identified compounds with significant inhibition effect of 50% and more21. These derivatives were further evaluated using a radioligand binding assay, and Ki values were calculated accordingly.

As shown in Tables 2–4, the greatest reduction in the inhibitory activity for spacer modified analogs was observed for compound 11b. For some serotonin receptors, this N-butyl analog has shown decreased inhibition (50–80%) when compared to penfluridol (95–100%) (Fig. 2), and for other serotonin receptor subtypes it retained inhibition levels at > 90% but decreased the Ki valued by 3–16-fold (Table 3). Comparable results were obtained for dopamine receptors, opioid receptors, NET, SERT and DAT (Fig. 3, Tables 4). Moreover, 11b has shown abolished activity at H1 and H2 receptors, significantly improving CNS-toxicity profile of the original penfluridol molecule. Similar effect was observed for compound 8a, a homologated analog of penfluridol. However, it appears that elongation of the chain doesn’t reduce the ability of this compound to inhibit dopamine receptors (Table 4). On a contrary, 8a produced significantly lower Ki values for D4 receptor subtype (Ki 25 nM) when compared to the original penfluridol molecule (Ki 10000 nM). An introduction of N-propyl linker, 11a, resulted in higher affinity of a molecule to histamine receptors and in substantially increased binding to the D4 receptor subtype, whereas the rest of the receptor’s groups were not affected. Available results for unsaturated analog 6 suggest that this compound has slight improvement in the CNS binding profile, although increased affinity to D4 receptor is observed here as well.

Table 2.

Binding activity (Ki, nm) of penfluridol and its analogs at serotonin receptor subtypes. Data represent mean inhibition (n = 4). NA - not active; ND - not determined.

5HT1A 5HT1D 5HT2A 5HT2B 5HT2C 5HT5a 5HT6 5HT7
PFL 356 3560 361 184 881 10,000 10,000 280
11a 1262 752 164 177 402 ND 1680 1574
8a 1395 844 1000 423 1712 894 1671 969
6 1363 NA 1105 2199 1603 ND ND 10,000
11b 1094 1074 6059 509 1126 4152 1670 812
8b 481 628 1000 374 2131 NA 1695 326
8c 10,000 10,000 900 729 740 4973 1400 949
13 901 4431 889 NA 2548 ND ND 1120
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Table 4.

Binding activity (Ki, nm) of penfluridol and its analogs at selected CNS receptors. Data represent mean inhibition (n = 4). NA – not active; ND – not determined.

KOR MOR DOR H1 H2 NET SERT DAT
PFL 10,000 867 1714 10,000 10,000 588 10,000 1714
11a 667 902 1558 814 252 902 903 1191
8a 2669 356 1413 ND 546 77 428 529
6 1021 328 ND 718 526 ND ND ND
11b 10,000 10,000 10,000 NA NA 458 10,000 10,000
8b 1328 70 1526 ND 278 518 1180 121
8c 10,000 8253 10,000 7031 NA 1438 1314 622
13 1705 536 NA 718 401 ND ND ND
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Fig. 2.

Fig. 2.

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Synthesized analogs of penfluridol with the corresponding activity against MDA MB231 and LLC cell lines.

Table 3.

Binding activity (Ki, nm) of penfluridol and its analogs at dopamine receptor subtypes. Data represent mean inhibition (n = 4). NA - not active; ND - not determined.

D1 D2 D3 D4 D5
PFL 147 159 136 10,000 125
11a 300 148 474 25 437
8a 798 194 209 385 529
6 ND 317 552 1643 ND
11b 10,000 550 782 10,000 744
8b 135 38 62 58 121
8c 10,000 417 437 459 623
13 ND 460 ND 132 ND
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Fig. 3.

Fig. 3.

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Inhibition of selected CNS receptors by penfluridol and its analogs. 5HT– serotonin receptors, D – dopamine receptors, KOR – kappa opioid receptor, MOR – mu opioid receptor, DOR – delta opioid receptor, H1-histamine receptor 1, H2 – histamine receptor 2, NET – norepinephrine transporter, SERT – serotonin trans-porter, DAT – dopamine transporter.

In the second group of analogs with the modifications on the left side of the diphenylbutylpiperidine structure, the most favorable profile is associated with the compound 8c. The data suggest a significant reduction in the Ki values for the majority of the serotonin and dopamine receptor subtypes, opioid receptors, and histamine receptors (Fig. 3, Tables 2–4). The monophenyl analog 13 has shown no substantial changes in the binding profile, whereas compound 8b lacking the 4-F substituent displays increased ability to inhibit all dopamine receptor subtypes, MOR, H2, and DAT. These data were not in line with the previously reported structure-activity relationship trends22,23, where the importance of the electron withdrawing groups at para-position was highlighted for the antipsychotic activity.

Overall, through the analysis of the receptor binding profiles, we were able to identify three compounds, 8a, 11b and 8c, with the reduced affinity to selected CNS receptors. Compounds 11b and 8c showed a significant reduction in the inhibition of dopamine receptors, a group of receptors strongly associated with the neurological side-effects produced by penfluridol. Similarly, 8a had pronounced effect on the inhibition of serotonin receptors, while moderate changes in the affinity to dopamine receptors. Therefore, we expect 8a, 11b and 8c to have diminished CNS toxicity if used as chemotherapeutic agents. Due to the minimal changes in the penfluridol structure, we assumed that our analogs yielded minimal alterations in the BBB permeability and no additional organ toxicity. To confirm this hypothesis, we have selected compounds 8a (IC50 4.8 μM, MDA MB231; IC50 4.2 μM, LLC) and 8c (IC50 6.1 μM, MDA MB231; IC50 7.1 μM, LLC) for further evaluation in vivo. The LLC cell line is a syngeneic cell line for mice of the C57BL6 background that have functional immune system30. Therefore, we have selected the C57BL6 mice (females) for our in vivo experiments. In the initial study, three groups of animals were treated with penfluridol, 8a or 8c compounds (5 mg/ kg) by intraperitoneal (i.p.) injection for seven consecutive days. This dosing regimen was chosen to match the published in vivo data, where seven days were reported as the minimum length of treatment for therapeutic effect in an in vivo lung cancer model31. Twenty-four hours after the last injection, all mice were sacrificed, and organs were collected and stored at −80 °C. LC-MS/MS analysis of plasma, brain, lungs and adipose tissue was performed to identify concentration levels of the compounds (Fig. 4). The observed distribution pattern for analog 8a was very similar to the one displayed by penfluridol, where an accumulation of the drug occurred predominantly in the adipose tissue and lungs. At the same time, compound 8a has higher level of the drug in the brain relative to penfluridol. Analog 8c, on the other hand, displayed lower concentration of the drug in all tested samples, although the overall distribution pattern was similar to penfluridol and 8a. Our preliminary analysis of the pharmacokinetic profile of 8c has shown that the maximum concentration of drug in the brain (Fig. S5, supplemental material) is achieved at a 6-hour time point following the i.p. injection of 10 mg/kg dose. Currently, we are investigating if lower levels of 8c in animal samples are associated with the faster metabolic degradation of this compound when compared to penfluridol. In particular, we are looking at the stability of the 4-methoxyphenyl moiety under experimental conditions.

Fig. 4.

Fig. 4.

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Concentration (nM) of tested drugs in selected organs after 7-day treatment of daily i.p administration (5 mg/kg), n = 5, * = P < 0.05, ** = p < 0.01, *** = p < 0.001, **** = p 0.0001.

None of the tested compounds had a significant effect on the organ weight (Fig. S6, supplemental material) supporting previously published data for penfluridol10. In addition, we performed clinical chemistry analysis of blood samples of the animals treated with penfluridol, compound 8a, and compound 8c (Fig. 5, Fig. S7). Specifically we measured the levels of electrolytes, minerals, protein metabolism (total protein, albumin, globulin, A/G ratio), kidney function (blood urea nitrogen – BUN), liver injury (including alanine aminotransferase – ALT, aspartate aminotransferase – AST, and glutamate dehydrogenase – GLDH), cholestasis, alkaline phosphatase (ALP), bilirubin, pancreatic function (amylase), and muscle injury (creatine kinase (CK), AST, ALT)32. In penfluridol-treated animals our results were consistent with the onset of hepatic stress or injury and inflammation of the GI tract. In fact, only penfluridol – treated animals have shown decreased BUN levels and increased GLDH corresponding to hepatic stress or injury, whereas decreased ALP levels may result from low zinc level or can be caused by inflammation of GI tract. None of these changes was observed in mice treated with compound 8c, thus suggesting that this analog have a better toxicity profile when compared to penfluridol.

Fig. 5.

Fig. 5.

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Effect of drug treatment (5 mg/kg, daily i.p. dosing for 7 days) on A. Kidney function: blood urea nitrogen (BUN); B. Liver injury: glutamate dehydrogenase (GLDH) and C. Liver injury: alkaline phosphatase (ALP), n = 5, * = p < 0.05, ** = p < 0.01.

To summarize, our study started with the evaluation of the potential CNS-related toxicity of penfluridol at the doses proposed for the anticancer therapy. As we have shown, this compound inhibits a majority of CNS-related GPCRs at the nanomolar level, raising concerns about a potential burden on a patient under treatment. In our study we have identified 2 compounds (8a and 8c) with anticancer activity but lesser CNS affinity (hence reduced CNS-related side effects) t when compared to penfluridol. In addition, these compounds have shown no toxicity in mice. The metabolic stability of these compounds and their utilization in metastatic triple-negative breast cancer model (8a) and lung cancer model (8c) is currently under investigation and data will be presented in due course. Furthermore, comparative side by side studies will be performed in the near future to evaluate the anticancer activity of these penfluridol analogs against commercially available treatments.

Supplementary Material

Supplemental data

Acknowledgments

Ki determinations and receptor binding profiles were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract # HHSN-271–2013-00017-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA.

This work was supported in part by the Laura W. Bush Institute for Women’s Health Seed Grant, TTUHSC, 2017.

Abbreviations:

ALP

alkaline phosphatase creatine kinase

ALT

alanine aminotransferase

AST

aspartate aminotransferase

BBB

blood brain barrier; BOC, tert-butoxycarbonyl

BUN

blood urea nitrogen test

CK

creatine kinase

CNS

central nervous system

D1–5

dopamine receptor subtypes

DAT

dopamine transporter

DCM

dichloromethane

DOR

delta opioid receptor

DPPH

1,1′-bis(diphenylphosphino)ferrocene

ESI

electrospray ionization

EtOH

ethano

FDA

Food and Drug Administration

GI

gastrointestinal

GLDH

glutamine dehydrogenase

H1–2

histamine receptor subtypes

5HT

serotonin receptors; IC50, half-maximum inhibitory concentration

i.p

intraperitoneal injection

Ki

inhibition constant

KOR

kappa opioid receptor

LC

liquid chromatography

LC-MS

liquid chromatography-mass spectrometry

LLC luc

mouse-derived luciferin expressing Lewis lung carcinoma cell line

MDA MB231

human triple-negative breast cancer cell line

MOR

mu opioid receptor

MTT

3-[4,5-dimethylthiazol-2-yl]-2,5-dimethyltetrazolium bromide

NET

norepinephrine transporter

NMR

nuclear magnetic resonance

r.t

room temperature

SERT

serotonin transporter

THF

tetrahydrofuran

TLC

thin-layer chromatography

Footnotes

☆

Authors on this paper have filed a provisional patent application (INV 1365, TTU, USA) detailing this work.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.bmcl.2018.10.036.

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