8-, 9-, and 11-Aryloxy Dimeric Aporphines and Their Pharmacological Activities

Aporphines, a major group of aporphinoid alkaloids, exhibit interesting and diverse pharmacological activities. A set of dimeric aporphines with an aryloxy group at C8, C9, and C11 have been isolated from six genera and shown to elicit various biological activities such as antitumor, antimalarial, antimicrobial, antiplatelet aggregation, antifibrotic, immunosuppressive, and vasorelaxant properties. In this review, the nomenclature, chemical structures, botanical sources, pharmacological activities, and synthetic approaches of this set of dimeric alkaloids are presented.

Aporphines are the main class of aporphinoid alkaloids. Their basic framework, as shown in Figure 1A, consists of four fused-ring systems with rings A, B, and D constituting an embedded 1-benzyltetrahydroisoquinoline. They can be further classified into four subgroups according to their chemical structure: aporphines sensu stricto, 6a,7-dehydroaporphines, 7-alkyl aporphines, and 7-oxygenated and/or 4-oxygenated aporphines [6]. Naturally occurring and synthetic aporphines possess a wide range of biological activities such as anticancer, anti-inflammatory, antioxidant, antiplatelet, anti-arrhythmic, antiprotozoal, antiplasmodial, antiviral, antibacterial, antimalarial, antiparkinsonian, and anticonvulsant properties [6]. Over the last few decades, several reviews covering the pharmacological activities of aporphines such as their antioxidant [8], cytotoxic [9][10][11][12], antiviral, antibacterial, and antifungal properties [13] as well as their dopaminergic, noradrenergic, and serotonergic activities [14][15][16] have been published. Additionally, the potent free radical scavenger properties of S-(+)-boldine (1) (Figure 1) and its numerous pharmacological activities have been reviewed [17,18]. Moreover, aporphine alkaloids have served as leads for the development of potential pharmaceutical products. For instance, the synthetic aporphine, R-(−)-apomorphine (2), shown in Figure 1, is a potent dopamine D 1 and D 2 receptor agonist that stimulates locomotor behavioral activity. This potent activity Dimeric aporphines are another class of aporphinoid in which two aporphinoid units are usually connected by either an ether or less frequently a carbon-carbon bond. According to the type and location of this bond, they can be divided into several subgroups [6,[23][24][25]: (1) Carbon-carbon bonded dimers, where the two aporphinoid units are coupled by a C-C bond. They include: i. Bisaporphines: the two aporphine units form either 7,7 -, 7,4 -, or 8,8linked dimers. ii.
Aporphine-benzylisoquinoline dimers (uskudaramine type): these compounds have a C-C bond between C8 of the aporphine unit and C11' of the benzylisoquinoline moiety.
(2) Ether-bonded dimers, where the two halves of the dimer are connected by an ether linkage. They include: i. Bisaporphines: the two aporphine units are linked together by an ether bond that may be formed between C1 and C2', C8 and C9', or C8 and C11'. ii.
Proaporphine-benzylisoquinoline dimers: this group includes pakistanamineand epivaldiberine-type dimers. The ether bond is located between C9 of the proaporphine moiety and C12' of the benzylisoquinoline unit in the case of pakistanamine-type dimers. However, it is located between C11 of the proaporphine unit and C12' of the benzylisoquinoline moiety in epivaldiberinetype dimers. iii.
Aporphine-phenyl (hernandaline-type) and proaporphine-phenyl (coyhaiquinetype) dimers: hernandaline-type dimers have a substituted phenyl ether linked to an aporphine moiety at C9. Additionally, the phenyl group can be connected to the aporphine unit at C1 or C8. On the other hand, coyhaiquine-type dimers possess a substituted phenyl ether connected to C9 of a proaporphine unit. These two rare subgroups are probably formed via the oxidation of the benzylisoquinoline half of the dimer into hydroxyl methyl, aldehyde, carboxylic acid, or ester-substituted phenyl ethers. iv.
Aporphine-protoberberine dimers: the protoberberine unit is coupled to the aporphine moiety at either C8 or C9. v.
Aporphine-benzylisoquinoline dimers: this is the largest subgroup of dimeric aporphines. Based on the nature of the tetrahydroisoquinoline moiety (S-reticuline or S-coclaurine), from which each monomer can be derived, and the location of the ether linkage between the two halves of the dimer, aporphine-benzylisoquinoline dimeric alkaloids can be divided into: (1) reticuline-reticuline dimers (thalicarpine and fetidine types), (2) reticuline-coclaurine dimers (istanbulamine and thalifaberine types), and (3) coclaurine-coclaurine dimers (pakistanine and kalashine types). Table 1 illustrates the position of the ether bond in each type. Table 1. Location of the ether bond in different types of aporphine-benzylisoquinoline dimeric alkaloids.

Chemical Structure Classification and Occurrence
A set of dimeric aporphines and 6a,7-dehydroaporphines with an aryloxy substituent at C8 have been mainly isolated from several species of the Thalictrum genus (Ranunculaceae) or Dehaasia triandra (Lauraceae). To the best of our knowledge, thirty-two compounds belonging to C8-aryloxy aporphines and six compounds belonging to C8-aryloxy 6a,7-dehydroaporphines have been reported to date. This set of compounds can be classified according to its chemical structure into four groups: (1) Bisaporphines: only two isolated bisaporphines ( Figure 2) with an ether linkage at C8 of one of the aporphine units have been reported. They were isolated in 1996 from the leaves of Dehaasia triandra. The first bisaporphine, named dehatriphine (3), has an ether linkage at the C8' position of isocorydine and the C9 position of N-methyllaurotetanine [26], while the second compound, named (11,8')-O-bisisocorydine (4), has two isocorydine units connected by an ether bond at C8' and C11 of the two units [27].

Chemical Structure Classification and Occurrence
A set of dimeric aporphines and 6a,7-dehydroaporphines with an aryloxy substituent at C8 have been mainly isolated from several species of the Thalictrum genus (Ranunculaceae) or Dehaasia triandra (Lauraceae). To the best of our knowledge, thirty-two compounds belonging to C8-aryloxy aporphines and six compounds belonging to C8-aryloxy 6a,7-dehydroaporphines have been reported to date. This set of compounds can be classified according to its chemical structure into four groups: (1) Bisaporphines: only two isolated bisaporphines ( Figure 2) with an ether linkage at C8 of one of the aporphine units have been reported. They were isolated in 1996 from the leaves of Dehaasia triandra. The first bisaporphine, named dehatriphine (3), has an ether linkage at the C8' position of isocorydine and the C9 position of N-methyllaurotetanine [26], while the second compound, named (11,8')-O-bisisocorydine (4), has two isocorydine units connected by an ether bond at C8' and C11 of the two units [27]. of the ether linkage between the two halves of the dimer, aporphine-benzylisoquinoline dimeric alkaloids can be divided into: (1) reticuline-reticuline dimers (thalicarpine and fetidine types), (2) reticuline-coclaurine dimers (istanbulamine and thalifaberine types), and (3) coclaurine-coclaurine dimers (pakistanine and kalashine types). Table 1 illustrates the position of the ether bond in each type. This review presents the nomenclature, chemical structures, botanical sources, pharmacological activities, and synthetic approaches of some types of ether-linked dimers. We focus our discussion on the naturally-occurring dimers in which an aporphine (including 6a,7-dehydroaporphines) unit is linked at C8, C9, or C11 via an ether linkage to either aporphine, pavine, protoberberine, phenyl, or 1-benzyltetrahydroisoquinoline units.

Chemical Structure Classification and Occurrence
A set of dimeric aporphines and 6a,7-dehydroaporphines with an aryloxy substituent at C8 have been mainly isolated from several species of the Thalictrum genus (Ranunculaceae) or Dehaasia triandra (Lauraceae). To the best of our knowledge, thirty-two compounds belonging to C8-aryloxy aporphines and six compounds belonging to C8-aryloxy 6a,7-dehydroaporphines have been reported to date. This set of compounds can be classified according to its chemical structure into four groups: (1) Bisaporphines: only two isolated bisaporphines ( Figure 2) with an ether linkage at C8 of one of the aporphine units have been reported. They were isolated in 1996 from the leaves of Dehaasia triandra. The first bisaporphine, named dehatriphine (3), has an ether linkage at the C8' position of isocorydine and the C9 position of N-methyllaurotetanine [26], while the second compound, named (11,8')-O-bisisocorydine (4), has two isocorydine units connected by an ether bond at C8' and C11 of the two units [27].

Dimeric Types Location of the Ether Bond 6a
Thalicarpine type C9 of the aporphine unit and C10' of the disubstituted 12',13'-benzylisoquinoline moiety This review presents the nomenclature, chemical structures, botanical sources, pharmacological activities, and synthetic approaches of some types of ether-linked dimers. We focus our discussion on the naturally-occurring dimers in which an aporphine (including 6a,7-dehydroaporphines) unit is linked at C8, C9, or C11 via an ether linkage to either aporphine, pavine, protoberberine, phenyl, or 1-benzyltetrahydroisoquinoline units.

Chemical Structure Classification and Occurrence
A set of dimeric aporphines and 6a,7-dehydroaporphines with an aryloxy substituent at C8 have been mainly isolated from several species of the Thalictrum genus (Ranunculaceae) or Dehaasia triandra (Lauraceae). To the best of our knowledge, thirty-two compounds belonging to C8-aryloxy aporphines and six compounds belonging to C8-aryloxy 6a,7-dehydroaporphines have been reported to date. This set of compounds can be classified according to its chemical structure into four groups: (1) Bisaporphines: only two isolated bisaporphines ( Figure 2) with an ether linkage at C8 of one of the aporphine units have been reported. They were isolated in 1996 from the leaves of Dehaasia triandra. The first bisaporphine, named dehatriphine (3), has an ether linkage at the C8' position of isocorydine and the C9 position of N-methyllaurotetanine [26], while the second compound, named (11,8')-O-bisisocorydine (4), has two isocorydine units connected by an ether bond at C8' and C11 of the two units [27].
This review presents the nomenclature, chemical structures, botanical sources, pharmacological activities, and synthetic approaches of some types of ether-linked dimers. We focus our discussion on the naturally-occurring dimers in which an aporphine (including 6a,7-dehydroaporphines) unit is linked at C8, C9, or C11 via an ether linkage to either aporphine, pavine, protoberberine, phenyl, or 1-benzyltetrahydroisoquinoline units.

Chemical Structure Classification and Occurrence
A set of dimeric aporphines and 6a,7-dehydroaporphines with an aryloxy substituent at C8 have been mainly isolated from several species of the Thalictrum genus (Ranunculaceae) or Dehaasia triandra (Lauraceae). To the best of our knowledge, thirty-two compounds belonging to C8-aryloxy aporphines and six compounds belonging to C8-aryloxy 6a,7-dehydroaporphines have been reported to date. This set of compounds can be classified according to its chemical structure into four groups: (1) Bisaporphines: only two isolated bisaporphines ( Figure 2) with an ether linkage at C8 of one of the aporphine units have been reported. They were isolated in 1996 from the leaves of Dehaasia triandra. The first bisaporphine, named dehatriphine (3), has an ether linkage at the C8' position of isocorydine and the C9 position of N-methyllaurotetanine [26], while the second compound, named (11,8 )-O-bisisocorydine (4), has two isocorydine units connected by an ether bond at C8' and C11 of the two units [27]. (2) Aporphine-protoberberine dimeric alkaloid: acutiaporberine (5) is the only known bisalkaloid of this class ( Figure 3). It was isolated in 2000 from the root of Thalictrum acutifolium (Hand.-Mazz.) Boivin [28]. (3) Aporphine and 6a,7-dehydroaporphine-phenyl dimeric alkaloids: thaliculine (6) and 6a,7-dehydrothaliculine (7), shown in Figure 3, represent the only reported examples to date with an ether bond at C8 of the aporphine unit. They were isolated together in 2019 from the roots of Thalictrum cultratum [29]. (4) Aporphine and 6a,7-dehydroaporphine-benzylisoquinoline dimers: this is the largest group of C8-aryloxy aporphines. To date, thirty-three members belonging to this group have been reported. The names, chemical structures, and botanical sources of these compounds are shown in Tables 2-5.
Lee and Doskotch [43] reported the isolation of two new benzylisoquinoline-aporphine dimers 39 and 40 (Table 5), which are structurally distinct from the thalifaberine-type dimers and do not belong to any of the other subtypes of benzylisoquinoline-aporphine dimers listed in Table 1. Both the aporphine and benzylisoquinoline units are reticuline-derived, and the ether linkage is between C11' of the monosubstituted 12 -benzylisoquinoline moiety and C8 of the aporphine unit, which is also oxygenated at C10 and C11.

Reported Synthetic Approaches for C8-Aryloxy Aporphines
Very few approaches for the synthesis of the 8-aryloxy aporphine scaffold have been reported. The earliest route for the formation of a non-naturally occurring ether-linked bisaporphine was described for the first time by Stuart and Callender in 1972 using enzymatic catalyzed oxidation (Scheme 1). Horseradish peroxidase was used to convert S-boldine (1) into bisboldine ether (41) and bisboldine (42) in 8% and 12% yields, respectively [47]. Another method for the synthesis of C8/C9' ether-linked bisaporphine was reported in 1978 (Scheme 2). Because of the potent activity of thalicarpine (43) as an anticancer agent and the need to understand its structure-activity relationship (SAR), Kupchan et al. reported the synthesis of three synthetic analogs; one of them was the bisaporphine 46. In their synthesis, the non-phenolic oxidative coupling of the tetrahydroisoquinoline unit of thalicarpine (43) using vanadium oxytrifluoride (VOF 3 ) gave the corresponding aporphineproaporphine dimers 44a,b, epimeric at C13, as two separable diastereomers in 72% and 5% yields, respectively. The sodium borohydride reduction of 44a furnished dienols 45a,b as two separable diastereomers in 75% and 15% yields, respectively. The dienol-benzene rearrangement of 45a with boron trifluoride etherate at 0 • C for 10 min gave bisaporphine 46 as the corresponding dihydrobromide salt in an 80% yield [48].
Because of the limited synthetic methods for 8-aryloxy aporphines and their dependence on non-abundant, naturally occurring aporphine derivatives (S-boldine (1), (+)-thalicarpine (43), and (+)-pakistanamine (47)) as starting materials, Ali et al. described an efficient synthesis of 8-phenoxy aporphine 52 as a model substrate for this subset of aporphine dimers by utilizing inexpensive and commercially available starting materials (Scheme 4). The synthesis featured the early stage installation of the required 8-phenoxy group via an aromatic nucleophilic substitution reaction (S N Ar), followed by the construction of the aporphine unit using modified Pictet-Spengler cyclization and Pd-XPhos-catalyzed ortho-phenol arylation as key steps in this synthesis to generate 8-phenoxy aporphine 52 in a 25% overall yield over six steps. The authors also reported the instability of 8-phenoxy aporphine 52 and its rapid oxidation to 6a,7-dehydroaporphine analog 53, which raises the possibility that some isolated 8-aryloxy-7-dehydroaporphines may not be naturally occurring and instead be formed through the air oxidation of their parent 8-aryloxy aporphines during various collection, storage, and/or processing operations [50].

Chemical Structure Classification and Occurrence
A group of aporphines and 6a,7-dehydroaporphines with an aryloxy group at C9 was isolated from several species of the Thalictrum genus (Ranunculaceae), the Hernandia genus (Hernandiaceae), the Berberis genus (Berberidaceae), Corydalis turtschaninovii Bess.

Thalicarpine-Type Dimers
This group, as discussed in Table 1, possesses an ether bond between C9 of the aporphine unit and C10 of the 12 ,13 -disubstituted benzylisoquinoline moiety. Additionally, dimers of this group possess (6aS, 1 S) absolute configuration. Twenty-four dimers of this type have been found in only two genera: Thalictrum (Ranunculaceae) and Hernandia (Hernandiaceae). Seventeen aporphine-benzylisoquinolines of the thalicarpine-type dimers 43 and 67-82 are listed in Table 7. The first member of this group, (+)-thalicarpine (43), was isolated by Kupchan et al. in 1963 [64], and its structure was revised by the same group two years later [65].

Istanbulamine-Type Dimers
As stated in Table 1, dimers of this group have an ether bond between C9 of the aporphine unit and C11' of the 12'-monosubstituted benzylisoquinoline unit, and they possess (6aS, 1 S) absolute configuration. The only two members of this group are listed in Table 11.

Pakistanine-Type Dimers
Dimers of this group, as described in Table 1, have a characteristic ether linkage between C9 of the aporphine unit and C12 of the benzylisoquinoline moiety. In contrast to dimers of the thalicarpine, fetidine, and istanbulamine types, these possess (6aR, 1 S) absolute configuration. Eight aporphine-benzylisoquinoline dimers of this type were isolated from the Berberis genus (Berberidaceae). Seven dimers of this type, 101-107, are listed in Table 12, and the structure of (+)-2 -norpakistanine (108), isolated from Berberis valdiviana Phil. [119], is shown in Figure 9.

New Type of Aporphine-Benzylisoquinoline Dimers
Seven aporphine-benzylisoquinoline dimers, 109-115, that do not fit into any dimeric types listed in Table 1 were isolated in 1998 by Zhang et al. [133]. Their chemical structures possess an ether bond between C9 of the aporphine unit and C11 of the 10 ,12 -or 12 ,14 -dimethoxy-substituted benzylisoquinoline moiety. Additionally, they have (6aS, 1 S) absolute configuration. Six members, 109-114, of this new type are listed in Table 13. Figure 10 depicts the structure of (+)-przewaline (115) characterized by an aromatic ring B of the aporphine unit.

Biological Activities of C9-Aryloxy Aporphines and 6a,7-Dehydroaporphines
Though most of the C8-aryloxy aporphines have shown significant cytotoxicity activities, only a few members of the C9-aryloxy aporphines have been reported to exhibit cytotoxic effects. Among them, thalicarpine is the most important member that entered into clinical trials.
In 1963, Kupchan et al. noted the transient hypotensive effects of thalicarpine (43) in cats with doses ranging from 0.5 to 5 mg/kg [135]. In subsequent studies with thalicarpine (43), Kupchan et al. reported that it had significant antitumor activity against Walker 256 carcinosarcoma in rats over a wide range of dosages [136][137][138]. Moreover, the in vitro cytotoxicities of some alkaloids from Thalictrum minus on a monolayer cell culture of KB cells were determined by measuring the degree of protein synthesis inhibition. Hernandaline (60), thalicarpine (43), and thalmelatine (67) showed 100% protein synthesis inhibition at a concentration of 100 µg/mL. However, dehydrothalicarpine (87) was devoid of activity [139]. In another study, thalicarpine (43) showed strong inhibitory activity against the HeLa-S3 cell line, with ED 50 = 2.5 µg/mL [140]. To understand the mode of action responsible for the antitumor activity of thalicarpine (43), Allen and Creaven showed that it has significant effects on macromolecular biosynthesis in cultured L1210 mouse leukemia cells at a concentration of 100 µM. It suppressed DNA, RNA, and protein synthesis by inhibiting the incorporation of thymidine, uridine, and leucine into DNA, RNA, and protein, respectively. Additionally, the authors stated that they could not detect any significant binding of thalicarpine (43) to calf thymus DNA using ultraviolet spectroscopy [137]. In a subsequent study using equilibrium dialysis, the same authors reported that tritiumlabeled thalicarpine (43) reversibly bound to calf thymus DNA in vitro. They also found that thalicarpine (43) did not bind to human serum albumin in vitro, but it did bind to an unidentified human serum component in vivo [141]. The in vitro inhibition of DNA, RNA, and protein synthesis by thalicarpine (43) and its binding to DNA was also reported in a later study by Creasey. The authors also found that treatment of mice bearing an S180 tumor with thalicarpine at doses of 30 and 60 mg/kg led to the 48 and 83% inhibition, respectively, of thymidine incorporation into DNA after 24 h [142]. Moreover, Allen and Creaven found that at relatively high concentrations of 0.1-0.5 mM, thalicarpine (43) inhibited rat liver microsomal aniline hydroxylase activity in vitro [143]. Based on its significant cytotoxicity activity in vitro, thalicarpine (43) (NSC 68075) was selected by National Cancer Institute (NCI) for clinical evaluation. It underwent numerous preclinical toxicological and pharmacological studies on mice, rats, cats, hamsters, dogs, and monkeys [144][145][146][147][148][149][150][151][152][153][154][155] before proceeding into initial clinical trials. Phase I clinical trials with 34 patients at a dose of 1400 mg/m 2 did not show promising antitumor activity, and the patients encountered adverse reactions of the central nervous and/or cardiovascular systems [156]. Allen et al. examined the plasma decay and urinary excretion of tritiated thalicarpine (43) in 19 patients at doses of 300-1900 mg/m 2 . They found that urinary excretion was very slow, with only 19.84% of the dose being excreted over 12 days in nine patients. The data indicated the prolonged body retention of thalicarpine (43), with significant localization in tissues. This raised the probability of dangerous drug accumulation if it is given at short dosage intervals [157]. Because of the absence of any hematologic, hepatic, and renal toxicity of thalicarpine during the phase I clinical trial, it entered into phase II trial with a recommended dose of 1100 mg/m 2 . Unfortunately, the results from 14 patients did not support further clinical investigation [158].
Though clinical trials of thalicarpine (43) were terminated, many research groups continued cytotoxic studies on this compound. For example, Todorov et al. found that thalicarpine (43) entrapped in negatively charged liposome carriers exhibited antitumor activity against Walker S and lymphoma TLX5 cell lines 2.5 times more potently than free thalicarpine (43) [159][160][161]. In 1980, Stoychkov et al. showed that thalicarpine (43) enhanced the antitumor activity of cyclophosphamide, a known antitumor drug, against sarcoma 37, Lewis lung carcinoma (LLC), and L1210 leukemia in mice. This synergetic effect was attributed to the different pharmacological behavior and mechanisms of action of the two drugs [162,163]. In a subsequent study, the combination therapy of cyclophosphamide with different cytotoxic drugs such as thalicarpine (43), carmustine (BCNU), lomustine (CCNU), 5-fluorouracil, and methotrexate in mice with lymphoid leukemia L-1210 showed that normally ineffective doses of cyclophosamide were active when combined only with thalicarpine (43). The other drugs exhibited either no synergetic effect or even decreased the antitumor activity of cyclophosphamide [164]. In 1992, the in vitro antitumor activity of thalicarpine (43) against cisplatin-sensitive and cisplatin-resistant rat ovarian tumor cell lines was examined, and the ID 50 values were found to be 39.3 and 27.3 µg/mL, respectively. Furthermore, combination therapy using cisplatin and thalicarpine (43) displayed an additive antitumor effect in cisplatin-sensitive cells but not cisplatin-resistant cells. The authors suggested thalicarpine (43) as a possible candidate for the treatment of cisplatinresistant ovarian tumors [165].
One of the major obstacles in cancer treatment is the development of drug resistance and even multidrug resistance (MDR). A commonly used technique to suppress the development of drug resistance is combination therapy in which two or more drugs acting by different modes of action and/or at different biomolecular targets can be used together. In a study by Gupta et al., sixty-two anti-cancer drugs were tested against puromycin resistant (Pur R ) mutants of HeLa cells to determine their ability to develop cross-resistance in this cell line. Thalicarpine (43) was one of the drugs that showed no cross-resistance and was suggested as a drug that can be used in combination therapy to overcome MDR [166]. Subsequently, the ability of thalicarpine (43) (43) partially inhibited the binding of tritiated azidopine with P-glycoprotein. These results indicated that thalicarpine's ability to overcome MDR via the enhancement of ADR cellular retention may be attributed to its interaction with P-glycoprotein efflux binding sites [167]. Numerous other studies on the mechanism of action of thalicarpine (43) reversing MDR in a variety of resistant cell lines such as cisplatin-resistant rat ovarian tumor cells [168][169][170], an Adriamycin-resistant human breast cancer cell line (MCF/AdR) [171,172], multidrug-resistant human colon carcinoma cells [173], multidrug-resistant mouse lymphoma cells [174], and doxorubicin (DOX)resistant HL-60 human acute myeloid leukemia (HL-60/DOX) [175]-as well as in artificial membranes composed of neutral and negatively charged phospholipids [176,177]-have been reported.
In 1988, the effect of methoxyadiantifoline (82) on the cardiovascular system was studied. It was found to increase the coronary blood flow in guinea pig hearts by 12.9% and 20.4% at 17 and 50 µM, respectively, and this action was accompanied by negative chronotropic and inotropic effects [178]. In another report, Jie et al. studied the effect of methoxyadiantifoline (82) on the physiological properties of the myocardium in isolated left and right rat atria. They found that at 30 µM, the functional refractory period of left atria muscles was prolonged from 61 to 90 ms after 15 min and contractility decreased to 50% after 40 min. Additionally, the rate and contractility of rat right atria were decreased to 60% and 50%, respectively [108]. In 1991, the in vitro antifibrotic activity of methoxyadiantifoline (82) was evaluated. The results showed that the compound displayed a significant binding affinity for membrane lipids and alveolar macrophages that resulted in its potent inhibition of zymosan-stimulated oxygen consumption (100% inhibition at 79 µM), superoxide release (85% inhibition at 79 µM), and hydrogen peroxide secretion (100% inhibition at 33 µM) by alveolar macrophages. The authors stated the potential effectiveness of methoxyadiantifoline (82) as an antifibrotic drug [179].
Chen et al. determined the in vitro anti-platelet aggregation effects of constituents from Hernandia nymphaeifolia. The results demonstrated that thalicarpine (43) completely inhibited both collagen (10 µg/mL) and platelet-activating factor (PAF; 2 nM)-induced platelet aggregation at 50 µg/mL. At the same concentration, hernandaline (60), showed the moderate inhibition of platelet aggregation induced by arachidonic acid (AA; 100 µM) and collagen (10 µg/mL) and the nearly complete inhibition of platelet aggregation induced by PAF. On the other hand, dehydrohernandaline (59) exhibited weak anti-platelet aggregation effects induced by AA, collagen, and PAF [57]. In another anti-platelet aggregation study, thalicarpine (43), at 100 µM, exhibited the nearly complete inhibition of platelet aggregation induced by collagen and the moderate inhibition of platelet aggregation induced by both AA and PAF [180].
In 2001, the in vitro vasorelaxant properties of constituents from Hernandia nymphaeifolia were studied by Chen et al. They found that hernandaline (60) (at 100 µM) completely inhibited aortic contraction induced by norepinephrine (3 µM) and only inhibited 27% of the aortic contraction induced by high K + (80 mM). However, 6a,7-dehydrohernandaline (59) exhibited no inhibitory activity due to the aromatization of ring C [181].
Recently, the immunosuppressive activity of twenty-one different isoquinoline alkaloids was tested in vitro on the concanavalin A (Con A)-stimulated proliferation of mice splenocytes. The aporphine-benzyl dimers (+)-thaliadine (61)
Because of the limited accessibility of those naturally occurring starting materials and the low yield of Ullman coupling reactions, Kupchan et al. presented an alternative strategy for thalicarpine (43) synthesis via the installation of the biaryl ether bond at an early stage of the synthesis. As illustrated in Scheme 6, diphenyl ether 120 was synthesized via an S N Ar reaction followed by the elaboration of the aporphine and benzyltetrahydroisoquinoline units to afford thalicarpine (43), though in only a 0.35% overall yield [186]. Some modifications in the formation of the aporphine unit from intermediate 120 enhanced the overall yield of thalicarpine (43) to 3% using the same strategy [187].
Despite the low yield of the Ullman coupling reaction, the late-stage installation of ether linkage has the advantage that the two units of the dimer may be separately synthesized as pure enantiomers, which allows for the structural and stereochemical variation of the two halves before the final coupling step. Due to this advantage, Cava et al. described an improved Ullmann diphenyl ether synthesis using pentafluorophenylcopper (PFPC) as the coupling agent, and its application in the syntheses of non-natural aporphine-benzylisoquinoline dimers 124 and 125 in 51% and 42% yields, respectively (Scheme 7) [188]. Scheme 5. Thalicarpine (43) and 6a,7-dehydrothalicarpine (87) syntheses via the late-stage installation of the ether bond using a classical Ullman coupling reaction followed by DDQ (2,3-dichloro-5,6dicyano-l,4-benzoquinone) oxidation. In 2019, Jean-Philip Lumb and coworkers reported a catalytic aerobic cross-dehydrogenative coupling reaction of phenols and catechols, and its application in thalicarpine (43) synthesis in 20% overall yield over 11 steps (longest linear sequence). As depicted in Scheme 8, the coupling of phenol 126 and catechol 127 using CuCl under an atmosphere of O 2 generated intermediate 128 in a 76% yield, which, after methylation and reduction, afforded thalicarpine (43) in a 74% yield over two steps [189]. On the other hand, the syntheses of naturally-occurring C9-aryloxy aporphines of the pakistanine-type dimers 101-107 were mainly achieved through the acid-catalyzed rearrange-ment of the naturally occurring proaporphine-benzylisoquinoline dimers of the pakistanaminetype dimers. As shown in Scheme 9A, heating proaporphine-benzylisoquinoline dimers 129, 47, and 130-133 in dilute hydrochloric acid furnished pakistanine-type dimers 101-106, respectively. However, the yields for these transformations were not reported [121,131,190]. Additionally, (+)-1,10-dimethylpakistanine (107) was synthesized in a 76-78% yield via the methylation of pakistanine-type dimers 101, 102, or 104 using an ethereal diazomethane solution [121,131].

Chemical Structure Classification and Occurrence
Only two 11-aryloxy aporphines (Table 14) of the kalashine-type dimers were isolated from the Berberis genus (Berberidaceae) to date. As stated in Table 1, kalashine-type dimers have an ether bond between C11 of the aporphine and C12 of the benzylisoquinoline unit, and they possess (6aR, 1 S) absolute configuration. There are no reported pharmacological activities for 11-aryloxy aporphines.

Summary
In this review, we reported the nomenclature, chemical structures, biological activities, and synthetic approaches of dimeric aporphines with an aryloxy substituent at C8, C9, or C11 of the aporphine unit. To the best of our knowledge, a total of ninety-seven dimers have been isolated from the Thalictrum genus (Ranunculaceae), Dehaasia triandra (Lauraceae), the Hernandia genus (Hernandiaceae), the Berberis genus (Berberidaceae), Corydalis turtschaninovii Bess. (Papaveraceae), and Tabernaemontana bufalina Lour. (Apocynaceae). The most represented class are C9-aryloxy aporphines and 6a,7-dehydroaporphines, while the C11-aryloxy aporphines are the rarest. Several members of these dimeric aporphines have exhibited cytotoxic activities. Only (+)-thalicarpine (43) entered clinical trials, which were terminated due to a lack of sufficient antitumor activity. In addition, some of these dimeric aporphines have shown antimalarial, antibacterial, antifibrotic, anti-platelet aggregation, vasorelaxant, and immunosuppressive activities, thus demonstrating the variety of pharmacology types that can be explored with this set of molecular scaffolds. Several synthetic approaches have been reported for the preparation of these natural products, such as the enzymatic catalyzed oxidation of aporphine and the photo-and acid-catalyzed rearrangement of naturally occurring proaporphine-benzylisoquinoline dimers. In addition, three approaches have been reported for the diaryl ether bond formation: (1) late-stage installation via the Ullman coupling of phenols and aryl halides; (2) late-stage installation through the catalytic aerobic cross-dehydrogenative coupling of phenols and catechols; and (3) early-stage installation using aromatic nucleophilic substitution reactions. However, additional opportunities for synthetic method development to access this class of natural products and the potential for generating non-natural derivatives remain.
Author Contributions: Conceptualization, collection of information, writing-original draft preparation and writing-review and editing, G.A. and G.D.C. All authors have read and agreed to the published version of the manuscript.

Funding:
The authors would like to thank the Welch Foundation (E-1916-20170325) for generous financial support for this research.