Abstract
We have previously reported the unique features of dimeric bisaminoquinolines as anticancer agents and have identified their cellular target as PPT1, a protein palmitoyl-thioesterase. We now report a systematic study on the role of the linker in these constructs, both with respect to the distance between the heterocycles, the linker hydrophobicity and the methylation status (primary vs. secondary vs. tertiary) of the central nitrogen atom on the observed biological activity.
Autophagy is a lysosome-dependent degradative pathway that cancer cells use to survive metabolic and therapeutic stress. Autophagy levels are generally high in melanoma and higher levels of autophagy are associated with poor survival.1 Induction of autophagy by cancer therapy occurs rapidly, providing immediate fitness to cancer cells facing therapeutic stress. Therefore, there is tremendous interest in targeting autophagy to improve the efficacy of cancer therapy.2 Clinical trials are underway with hydroxychloroquine (HCQ), but new agents are needed that can effectively inhibit autophagy.
The synthesis of dimeric analogs of CQ that have been designed to take advantage of the thermodynamic benefits associated with polyvalency has been studied for more than two decades. 3 The activity of these dimeric chloroquines (DC) against CQ resistant malaria has been attributed to their steric bulk, which can preclude incorporation into the chloroquine resistance transporter.4 Alternatively, it has been proposed that the DCs may be more efficiently trapped in the acidic digestive vacuole because of the additional positive charges resulting from nitrogen protonation under physiological conditions.5 More recently, the application of this strategy to cancer chemotherapeutics has led to the discovery of improved cytotoxicity by covalently linking fluorinated quinolines with AKT inhibitors.6 Solomon and coworkers have shown that formation of dimeric quinolines using a piperazine-based linker led to compounds with potent anti-cancer activity. And, subsequent to our first disclosures on the synthesis and study of dimeric quinolines, Carew and Nawrocki have reported chloroquine-lucanthone conjugates with anticancer activity.7 These results suggested to us that dimeric chloroquines (DCs) could form the basis for a new approach to the development of cancer chemotherapies.
We have previously reported a series of more potent dimeric chloroquine (DC) and dimeric quinacrine (DQ) derivatives: Lys05 (DC221),8 DQ661,9 and DC661.10 The names of these DC and DQ structures are generated using three digits as with numerical identifiers (m, n, R), where m and n signify the number of carbons to the left and right of the central nitrogen of the triamine linker, respectively, and the R signifies the methylation status of the central nitrogen of the linker, where 1 is methylated (tertiary amine) and 0 is unmethylated (secondary amine) (Figures 1A and 1B).
Figure 1.
Known properties of dimeric chloroquines and dimeric quinacrines. A. Generic structure of dimeric chloroquines B. Effect of linker carbon length on inhibitory potencies C. Generic structure of dimeric quinacrines and effect of central nitrogen methylation on autophagy and DNA damage with dimeric quinacrines. (For both 1B and 1C, m, n, and R are defined in the text).
We have shown that each of these compounds binds to and inhibits the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1), which regulates palmitoylation-mediated intracellular trafficking of the vacuolar ATPase.9–10 PPT1 inhibition with DCs or DQs deacidify the lysosome and inhibit autophagy. Our previously reported DC and DQ series consist of a triamine linker that unites either quinoline or quinacrine rings, respectively. Two structural features of these compounds are critical to their increased potency relative to HCQ: 1) length of the linker between the two quinoline rings, and 2) central nitrogen methylation status.
We found that increasing the number of carbons in the linker, from DC221, which has a seven-atom triamine linker, to DC661 (Figure 1A, 1B), which has a fifteen-atom triamine linker, improved autophagy inhibition and antitumor activity of the compounds.10 The second observation, previously only reported in the DQ series, 9 was that methylation of the central nitrogen led to preferential localization to the lysosome compared to compounds where the central nitrogen was not methylated. For example, DQ660 localized to the nucleus, producing DNA damage and autophagy induction, whereas DQ661 (which has a similar pKa as DQ660) localized to the lysosome and inhibited autophagy. We describe herein studies on the importance of these two factors, central nitrogen methylation and the combination of linker length and hydrophobicity, on the autophagy inhibition and anticancer properties of the dimeric chloroquines (DCs).
One of the most striking findings of our previous studies in the DQ series was the remarkable selectivity in subcellular localization imparted by a single methyl group (R=CH3; Figure 1C). A DQ compound with a secondary amine, DQ660 3 (R=H), localized to the nucleus producing DNA damage, and induced autophagy while the analogous tertiary amine DQ661 4 (R= CH3) localized selectively to the lysosome and inhibited autophagy. This difference was assessed using classical autophagy markers LC3 and SQSTM1/p62 to distinguish amongst compounds that could induce or inhibit autophagy, and phosphorylation of H2AX to detect DNA damage, i.e., nuclear localization. 9
In order to better understand the structural features that imparted improved potency and lysosomal inhibition going from DC221 1 to DC661 2 in the dimeric chloroquine series, as well as the role of central nitrogen substitution on temporal localization in the cellular milieu, we designed and synthesized a series of novel derivatives of DC221 1 and DC661 2. We performed cell viability assays along with immunoblotting in whole cell lysates against autophagy and DNA damage markers to assess the effects of chemical structural changes, i.e., linker length and nitrogen substitution, within the DC series on biological activities in a melanoma cell line.
Design and synthesis of compounds to test the relative importance of linker hydrophobicity versus linker length.
To determine the relative importance of hydrophobicity vs. the length of the linker between the two quinoline rings in the dimeric chloroquines (DCs), we prepared a series of new compounds in which we varied both the linker length as well as the hydrophobicity of linker. We reasoned that comparison of DC228-C 6 with DC661 2 would allow us to determine the role of the distance between the two heterocycles on the biological activity of these dimeric structures, using structures of otherwise comparable overall hydrophobicity. The addition of eight carbon atoms to the central nitrogen atom of DC221 1, as shown in DC228-C 6, retains the same shorter linker length of DC221 1 while at the same time approximating the increased hydrophobicity of DC661 2 by using roughly the same number of total carbon atoms in the linker (12 carbons in DC228-C 6 vs. 13 carbons in DC661 2) (Figure 2). We also prepared DC228-P 7, with a polyethylene glycol substituent in the place of the n-octyl group, with the expectation that it would be less hydrophobic than DC228-C 6 due to the presence of the polyethylene glycol linker in lieu of the n-octyl side chain. The synthesis of DC228-C 6 and DC228-P 7 was achieved by reductive alkylation [NaBH(OAc)3] of the previously described DC220 58 with 1-nonanal or 2-(2-ethoxyethoxy) acetaldehyde, respectively.
Figure 2.
Chemical structures of novel dimeric chloroquines 6,7,9 and10
The homologous analogs DC668-C 9 and DC668-P 10 were analogously prepared via the same reductive alkylation steps starting from the previously described DC660 810. Here we reasoned that further increasing the hydrophobicity of DC661 2 by replacing the methyl substituent on the central nitrogen atom of the linker with either n-octyl or polyethylene glycol sidechains, respectively, would allow us to probe the role of increasing the hydrophobicity in the longer linker series without further perturbing the distance between the chloroquine moieties.
Reducing linker length while maintaining overall hydrophobicity (DC228-C vs. DC661) does not lead to abrogation of autophagy inhibition or cytotoxicity.
A375P melanoma cells were treated for 24 hours with the following compounds: DC661 2, DC668-C 9, DC668-P 10, DC221 1, DC228-C 6, and DC228-P 7. Immunoblotting against autophagy markers LC3B, SQSTM1/p62, BNIP3 was performed on the lysates (Figure 3A). LC3B is a protein that is conjugated to lipid on the forming autophagic membrane, making it the canonical marker for autophagic vesicle content in cells. When LC3B is conjugated to lipid on forming autophagic vesicle membrane by the autophagy conjugation system (LC3B-II), it migrates faster in a SDS-PAGE than its unconjugated form (LC3B-I). When autophagic vesicles accumulate following lysosomal blockade LC3II/LC3I levels increase.11 p62 and BNIP3 are both autophagy cargo receptors that become sequestered with their cargo in the autophagic vesicles and degraded in the lysosome when autophagic flux is functional or induced. Increased levels of LC3BII/LC3BI, p62, and BNIP3 reflect autophagy inhibition. DC661 2 produced the expected increase in LC3B, p62 and BNIP3, reflecting autophagy inhibition (Figure 3A). Treatment of cells with DC668-C 9, which has 8 carbon chain attached to the central nitrogen of DC661 2, produced similar autophagy inhibition as DC661 2. DC668-P 10, which has an 8 atom polyethylene glycol chain attached to the central nitrogen of DC661 1, produced slightly improved autophagy inhibition compared to DC661 2, suggesting that the reduced hydrophobicity expected for DC668-P 10, compared to DC668-C 9, resulted in improved lysosomal penetration. DC221 1, the parent structure with the shortest linker between the two quinoline rings, produced less autophagy inhibition than DC661 2. DC228-C 6, in which 8 carbons were added to the central nitrogen of DC221 1, thereby mimicking the overall hydrophobicity of DC661 2 but with a shorter linker length, exhibited improved autophagy inhibition compared to DC221 1, and was equal to or better than that observed with DC661 2 (Figure 3A). Unlike DC668-P 10, DC228-P 7, which has a PEG chain attached to the central nitrogen methyl group of DC221 1, reducing hydrophobicity compared to DC228-C 6, did not lead to increased autophagy inhibition relative to DC221 1. To determine if any of these changes in autophagy inhibition found with changing linker length or hydrophobicity was associated with changes in cell viability, a 72 hour MTT assay was performed in A375P cells [Figure 3B and Supplemental Table 1 (see Supporting Information)]. All of the DC661 derivatives (DC661 2, DC668-C 9, DC668-P 10) had similar submicromolar IC50s. The increased autophagy inhibition observed with DC228-C 6 relative to DC221 1 did not result in a sub-micromolar IC50, although the IC50 was significantly decreased compared to that of DC221 1. Therefore, although addition of an extended carbon chain to the central nitrogen of the DC with the shorter linker imparted similar lysosomal autophagy inhibition properties to those of the DCs with longer linkers, this did not fully translate into similar levels of cytotoxicity. This finding suggests that DCs with longer linkers offer better anticancer properties than DCs with shorter linkers, even when additional carbon substituents are added to the central nitrogen of the shorter linkers.
Figure 3.
Effects of chain extension of dimeric chloroquine central nitrogen on autophagy inhibition and cell viability. A. A375P cells were treated with 3 μM of the indicated compounds for 24 hours. Whole cell lysates were immunoblotted for the indicated proteins. The experiment was repeated 3 times. Quantification of a representative blot is provided below each lane. B. Mean IC50s values with standard error of the mean of the indicated compounds calculated from 72 hours MTT assays in A375P cells performed 3 times. *p<0.01 to 0.05 **p<0.001 to 0.01 ***p<0.0001 to 0.001 ****p<0.00001; ns: not significant.
Design and synthesis of compounds to test the role of secondary versus tertiary amines
One of the most striking findings of our previous studies was the remarkable selectivity imparted by a single methyl group in molecular localization, with secondary amines such as DC660 8 (Figure 2) localizing to the nucleus and the tertiary amine DC661 2 localizing selectively to the lysosome. The subtle difference in basicity between secondary and tertiary amines suggested that the observed selectivity could not be attributed to selective affinity for the acidic microenvironment of the lysosome. One clear difference between the secondary and tertiary amine-containing compounds is that the secondary amines can participate in Schiff base formation, i.e., condensation of the amine with a biological aldehyde or ketone functionality, while the tertiary amines cannot. To explore whether these structural differences formed the basis for the observed selectivities, we introduced an additional amine moiety into DC221 1, as either a primary, secondary or tertiary amine, in the form of DC222-N 11 (primary amine), DC222-N01 12 (secondary amine), and DC222-N02 13 (tertiary amine), respectively (Figure 4). We reasoned that the presence of a reactive amine functionality (primary or secondary) could subvert the previously observed lysosomal targeting achieved with DC221 1 and generate a compound that could localize to the nucleus. These compounds were prepared by reductive alkylation of DC220 5 (Figure 2) with N-Boc-2-aminoacetaldehyde or N-Boc-N-methyl-2-aminoacetaldehyde, respectively, followed by nitrogen deprotection (TFA) to generate DC222-N 11 and DC222-N01 12, respectively. Subsequent methylation [aqueous formaldehyde, NaBH(OAc)3] of 12 afforded the tertiary amine DC222-N02 13.
Figure 4.
Chemical structures of novel dimeric chloroquines 11–13
Tertiary amine functionality is critical for autophagy inhibition and cytotoxicity with dimeric chloroquines.
A375P melanoma cells were treated for 24 hours with the following compounds: DC660 8, DC661 2, DC220 5, DC221 1, DC222-N 11, DC222-N01 12, DC222N02 13, DC228-C 6, and DC228-P 7. Immunoblotting against autophagy markers LC3B, SQSTM1/p62, BNIP3 was performed on the lysates (Figure 5A). DC660 8, an unmethylated DC with the longer linker, did not produce elevation in p62 or BNIP3, unlike DC661 2, suggesting that it was a less potent autophagy inhibitor than DC661. In addition, DC660 8, but not DC661 2, produced substantial phosphorylation of H2AX, reflecting DNA damage. Thus, similar to what we previously reported with DQ660 and DQ661,9 treatment of melanoma cells with DC661 2, which contains a tertiary amine at the central nitrogen position of the linker (R=Me; Figure 1), facilitates lysosomal localization and autophagy inhibition (Figure 5A). In contrast, DC660 8, which contains a secondary amine (R=H) at the central linker nitrogen, produced DNA damage and autophagy induction. DC220 5, containing the shorter linker with a central secondary amine, produced less autophagy inhibition than DC221 1 (tertiary amine, R=Me). Unlike DC660 8, DC220 5 did not produce phosphorylation of H2AX, suggesting that increased linker length was also important for the production of detectable DNA damage in the unmethylated (secondary amine, R=H) DC series. Placement of a primary or secondary amine-containing moiety (2-aminoethyl in DC222-N 11 or N-methyl-2-aminoethyl in DC222-N01 12, respectively) on the central nitrogen of the linker abrogated the autophagy inhibition observed with DC221 1, and did not produce DNA damage. The addition of a second tertiary amine-containing functionality to the central nitrogen atom of DC221 1 (i.e., DC222-N02 13) produced similar autophagy inhibition as was observed with DC221 1. To further confirm the effects of primary, secondary, and tertiary amines on autophagic flux, we generated and used the mCherry-eGFP-LC3B A375P autophagy reporter cells. We treated these cells with vehicle, DC220 5, DC221 1, DC222-N 11, DC222-N01 12, DC222-N02 13 (Figure 5B). This reporter cell line leverages that fact that when the mcherry-eGFP-LC3 protein is conjugated to emerging autophagy vesicles it allows the possibility of distinguishing induction of from inhibition of autophagic flux.When autophagic flux is induced by a compound, the mCherry-eGFP-LC3B molecule enters a functional lysosome and the GFP signal is quenched by the acidic environment in the lysosome. This results in the accumulation of red puncta reflecting autophagy induction. In contrast, if the lysosome is inhibited and autophagic flux is blocked, then green and red fluorescence converged to yield yellow puncta. DC220 produced an increase in red puncta. DC221 1 produced yellow puncta. Neither DC222-N 11, nor DC222-N01 12 produced significant accumulation of yellow puncta indicating that adding a primary or secondary amine to the central nitrogen methyl group abrogates the ability to inhibit autophagic flux. In contrast, DC222-N02 13, in line with the immunoblotting results in Figure 5A, yellow puncta can be asily seen in nearly every cell reflecting the addition of a tertiary amine to the central nitrogen methyl group rescues lysosomal inhibition. To determine how the differences in autophagy inhibition observed with these compounds correlated with cytotoxicity, 72 hour MTT assays were performed with the DC22x series (Figure 5B, Supplementary Table 1). As reflected by the immunoblotting, cytotoxicity of the two tertiary amine-containing DC compounds, DC221 1 and DC222-N02 13, was nearly equivalent and significantly better than that observed with DC220 5, DC222-N 11, or DC222-N01 12, which contain either primary or secondary amine functionalities, respectively (Figure 5C). Taken together, these results indicate that the tertiary amine functionality, that is present in DC221 1, DC661 2, and DC222-N02 13, is critical for both autophagy inhibition and cytotoxicity.
Figure 5.
Effect of the addition of primary, secondary or tertiary amines to central nitrogen methyl group of dimeric chloroquines. A. A375P cells were treated with the indicated compounds for 24 hours. Lysates were immunoblotted for the indicated proteins. The experiment was repeated 3 times. Quantification of a representative blot is provided below each lane. B. mCherry-egfp-LC3B A375P cells were treated with vehicle or 10 μM of the indicated compounds for 24 hours. Representative fluorescent miscope images are presented. Red puncta (red arrows) reflect induction of autophagic flux; yellow puncta (Yellow arrows) reflect inhibition of autophagic flux. C. Mean IC50 with standard errorof the mean for each of the indicated compounds calculated from 72 hours MTT assays in A375P cells. Experiments were performed 3 times. *p<0.01 to 0.05 **p<0.001 to 0.01 ***p<0.0001 to 0.001; ns: not significant.
We have prepared a series of dimeric chloroquines (DC) to investigate the roles of both linker composition and nitrogen substitution on both autophagy inhibition and cytotoxicity. A positive correlation between linker length and potency has been established. To determine the relative importance of total carbon number (hydrophobicity) vs. linker length, we have modified the structure of DC661 2 by shortening the linker to that of DC221 1 while increasing the number of carbons attached to the central nitrogen atom of the linker to generate DC228-C 6. The hydrophobicity of DC228-C 6, as calculated by LogP (octanol-water partition coefficient),12 is 7.58, compared to 8.72 for DC661 2 and 4.1 for DC221 1. These values are consistent with similar hydrophobicities for DC661 2 and DC228-C 6. We observed increased autophagy inhibition with DC228-C 6 relative to DC221 1 (Figure 2A), establishing that increasing hydrophobicity without changing linker length leads to increased potency. However, the increased autophagy inhibition observed with DC228-C 6 did not lead to submicromolar cytotoxicity (Figure 2B), although there was a substantial difference between the cytotoxicity of DC228-C 6 and DC221 1. Therefore, although addition of the n-octyl substituent to the central nitrogen atom of DC221 1 did impart similar lysosomal autophagy inhibition properties as were observed with the longer linker, i.e., DC661 2, the cytotoxicity levels of DC228-C 6 did not reach those observed with DC661 2, suggesting that DCs with longer linkers such as DC661 2 offer improved anticancer properties relative to the DCs with shorter linkers, such as DC221 1 and DC228-C 6. Changing the central nitrogen substituent from the n-octyl moiety in DC228-C 6 to the polyethylene glycol moiety in DC228-P 7 led to an enhancement of autophagy inhibition, an indication of the subtle interplay between hydrophobicity and lysosomal penetration.
One of the hallmarks of our studies of the dimeric quinolines (DC) and quinacrines (DQ) has been the striking effect of the methylation status of the central nitrogen atom of the linkers. We have observed lysosomal targeting with the tertiary amine-containing substrates such as DC221 1 and DC661 2, and nuclear localization with the secondary amine-containing substrates such as DC220 5 and DC660 8. Because of the negligible difference in pKa between secondary and tertiary amines, we reasoned that a functional difference between the two series must be responsible for these effects, possibly Schiff-base formation, which could occur with the DC220 5 and DC660 8 (secondary amine) but not DC221 1 and DC661 2 (tertiary amine). To test this idea, we prepared analogs of DC221 1, in which the central N-methyl substituent was replaced with a 2-aminoethyl moiety (DC222-N 11, primary amine), an N-methyl-2-aminoethyl moiety (DC222-N01 12, secondary amine), or an N, N-dimethyl-2-aminoethyl moiety (DC222-N02 13, tertiary amine). As shown in Figure 4, we have found that introduction of either primary or secondary amino functionality, i.e., DC222-N 11 or DC222-N01 12, into the structure of DC221 1 led to abrogation of autophagy inhibition. However, with DC220 5 we did not observe DNA damage, our previously described marker of nuclear localization, indicating that the secondary amine of DC220 5 is necessary but not sufficient for nuclear localization, which we observed only with increased linker length, i.e., DC660 8. As reflected by the immunoblotting, cytotoxicity of the two tertiary amine-containing DC compounds, DC221 1 and DC222-N02 13, was nearly equivalent and significantly better than that observed with DC220 5, DC222-N 11, or DC222-N01 12, which contain either primary or secondary amine functionalities. These results clearly indicate the advantages of the tertiary amine functionality for maximal cytotoxicity.
These results support our previous findings regarding the importance of increased hydrophobicity on both autophagy inhibition and cytotoxicity, although a clear difference exists between the cytotoxicities observed with DC661 2 (superior) and DC228-C 6, supporting the importance of increased separation (longer linkers) of the quinolines for optimal activity. The results that we have obtained with DC222-N 11, or DC222-N01 12 support our model for the importance of the nitrogen methylation of DC221 1 and DC661 2 (tertiary amine) compared to DC220 5 and DC660 8 (secondary amine). Further studies directed toward the optimization of these structures are currently underway in our laboratory and our results will be reported in due course.
Supplementary Material
Acknowledgements
This work was supported by NCI grants P01CA114046 (R.K.A. and J.D.W.) and P30 CA016520 (R.K.A).
Footnotes
Supporting Information
General information and methods, a list of abbreviations for the solvents and reagents used, experimental procedures and analytical data for all new compounds, NMR spectral data (1H and 13C) for all new compounds, and a supplementary table including IC50 data
Conflict of Interest Statement: JDW and RKA are inventors on patents on dimeric chloroquines and dimeric quinacrines (US Patent Numbers 61/480,64; 62/034,897; 15/567,18). These have been licensed to Pinpoint Therapeutics. JDW and RKA are co-founders of Pinpoint Therapeutics.
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References and Notes
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