Synthesis and biological evaluation of a novel acronycine/duocarmycin hybrid natural product

Article abstract of DOI:10.3987/COM-12-S(N)37

The design of novel natural product hybrids consisting of parts of two or more bioactive compounds may allow an access to new drugs. Here we describe the synthesis of 3, a hybrid of the cytotoxic acronycine (2) and seco-duocarmycin (seco-1), which was prepared Via a selective bromination of 7 followed by the introduction of an alkyne moiety, which was further manipulated to give the epoxide 12. Cyclisation and chlorination of the formed primary hydroxy group yielded 3, which in situ would give the desired hybrid 4. The in-vitro-cytotoxicity test revealed a slightly higher bioactivity of the hybrid 3 compared to acronycine (2).

Full text of DOI:10.3987/COM-12-S(N)37

HETEROCYCLES, Vol. 86, No. 1, 2012
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HETEROCYCLES, Vol. 86, No. 1, 2012, pp. 425 - 433. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 18th June, 2012, Accepted, 18th July, 2012, Published online, 7th August, 2012
DOI: 10.3987/COM-12-S(N)37
SYNTHESIS AND BIOLOGICAL EVALUATION OF A NOVEL
ACRONYCINE/DUOCARMYCIN HYBRID NATURAL PRODUCT
Lutz F. Tietze,* Arne Heins, Johannes R. Reiner, Svenia-C. Duefert, and
Ingrid Schuberth1
1
Institute of Organic and Biomolecular Chemistry, Georg-August University
Goettingen, Tammannstr. 2, 37077 Goettingen, Germany
E-mail: ltietze@gwdg.de
Abstract – The design of novel natural product hybrids consisting of parts of two
or more bioactive compounds may allow an access to new drugs. Here we
describe the synthesis of 3, a hybrid of the cytotoxic acronycine (2) and
seco-duocarmycin (seco-1), which was prepared via a selective bromination of 7
followed by the introduction of an alkyne moiety, which was further manipulated
to give the epoxide 12. Cyclisation and chlorination of the formed primary
hydroxy group yielded 3, which in situ would give the desired hybrid 4. The
in-vitro-cytotoxicity test revealed a slightly higher bioactivity of the hybrid 3
compared to acronycine (2).
INTRODUCTION
Nature is an excellent source of lead structures for the fight against any type of disease. In fact,
approximately 42% of the drugs that have been approved in the last 25 years are either natural products or
derivatives and analogues thereof.1 For anti-cancer agents the percentage is even higher, 52% of the
approved drugs are nature derived and nearly all immunosuppressive drugs needed in transplantations are
natural products or their derivatives.1 Although the number of natural products being huge in the end it is
limited, whereas millions of hybrids as combinations of parts of different natural products can be
prepared. Recently, we and others have introduced the concept of natural product hybrids and shown its
usefulness. Thus, these hybrids often exceed their parent compounds in biological activity or have other
useful properties.2 One example for a natural hybrid is the indole alkaloid vincristine,3 a well known drug
in cancer chemotherapy. It is a dimeric indole alkaloid consisting of vindoline – an alkaloid of the
Aspidosperma subgroup – and catharanthine – a member of the Iboga subgroup of indole alkaloids.
Dedicated to Professor Dr. Ei-ichi Negishi on the occasion of his 77th birthday.

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Interestingly, both monomers do not show any useful biological activity. In our approach for a selective
treatment of cancer on the basis of the antibody directed enzyme prodrug therapy (ADEPT) we also used
hybrids which consist of analogous of the antibiotic duocarmycin SA (1) and a sugar moiety (figure 1).4
Here a reduction of the cytotoxicity is the goal.
In our search for new anti cancer compounds with better tolerance we here describe the preparation of a
new hybrid of duocarmycin SA (1) in its seco-form with the acridone alkaloid acronycine (2), which was
first isolated from Acronychia baueri Schott (Rutaceae) in 1948 (Figure 1). Acronycine (2) shows a broad
spectrum of activity against numerous cancer models and its cytotoxicity is based on an intercalation with
double stranded DNA due to its planar aromatic system which is followed by an alkylation probably via
the intermediate formation of an epoxide.5 However, clinical trials employing 2 and benzo[b]acronycine,
respectively gave only poor results mainly because of their moderate potency and low water-solubility.6
Cl
OMe
OMe
OMe
OMe
N
N
N
N
MeOOC
MeOOC
H
H
OMe
OMe
O
O
N
H
N
H
O
OH
1
seco-1
O
N
OMe
O
OH
O
O
O
N
H
N
O
O
H
2
3
4
Cl
Figure 1. Natural products duocarmycin SA (1) and acronycine (2), seco-duocarmycin (seco-1) and
hybrid compounds 3 and 4.
On the other hand, duocarmycin SA (1), isolated in 1986 from Streptomyces sp. DO-113, shows a very
high cytotoxicity with an IC50 = 10 pM,7 but has severe side effects such as myelotoxicity.8 The
spirocyclopropylcyclohexadienone moiety together with the DNA-binding unit in duocarmycin SA (1)
and similar compounds allows an irreversible intercalation into the minor grove of the DNA to induce
apoptosis.4
For a combination of the positive effects of duocarmycin SA (1) and acronycine (2), we designed the
novel acronycine/seco-duocarmycin hybrid 3, which would be transformed in situ by a Winstein
cyclisation9 into the active hybrid natural product species 4, comprising the acridone structure of
acronycine (2) and the spirocyclopropylhexadienone moiety of duocarmycin SA (1).

HETEROCYCLES, Vol. 86, No. 1, 2012
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RESULTS AND DISCUSSION
Synthesis of a novel acronycine/duocarmycin hybrid natural product 4: Our approach for the
synthesis of 4 was based on the formation of the chloride 3 from the hydroxy compound 13, which on the
other hand should be accessible from 12 containing an aryl bromide and an epoxide moiety. Thus,
halogen-metal exchange followed by a nucleophilic attack with opening of the epoxide would directly
lead to 13. However, all attempts to transfer 8 into 12 in a straight forward approach using for instance the
methanesulfonate of the epoxide of 1,1-dimethylallylic alcohol were not successful, since under the
reaction conditions only the corresponding propenyloxirane was formed. Therefore, we used
3-chloro-3-methylbutyne for the alkylation of 8 with further manipulations to give 12. At this stage we
did not try to develop an enantioselective synthesis, since we did not know which of the two enantiomers
would be more active.
Commercially available 2-hydroxynaphthoic acid (5) was reacted with zinc chloride in aqueous, saturated
ammonia solution at 190 °C for 4.5 d to give the amino acid 6 in 60% yield.10 Fusion with phloroglucinol
(1,3,5-trihydroxybenzene) using catalytic amounts of tosylic acid in n-heptanol under reflux for 19 h led
to the acridone 7 in 59% yield.11 Selective bromination at C-4 was achieved via a complexation of the
vinylogous acid functionality with zinc chloride and subsequent addition of one equivalent of NBS in
acetone at –78 °C for 2 h to give 8 in 59% yield. In addition, 15% of the 2-bromo derivative and 4% of
the dibromo compound besides 18% of the starting material were obtained. The yield of 8 could be
improved to 70% using 1.35 equivalents of NBS under otherwise identical reaction conditions with the
disadvantage of the additional formation of 18% of the dibromo compound which was difficult to
separate from 8. Other complexing agents as CuCl2 afforded lower yields of 8. Interestingly, reaction of 7
with 1.00 equivalent of NBS at –78 °C without the addition of ZnCl2 gave the unwanted 2-bromo
compound as the main product with 43% yield. Monoalkylation with 3-chloro-3-methyl-1-butyne using
catalytic amounts of copper(I) chloride in DMF at rt for 24 h yielded 9 in 68%. For this transformation
the use of a Zn-salt as ZnBr2 as an additive was less appropriate, since only 6% of the desired 9 was
obtained, the main product with 34% was a pyran which is probably formed from 9 by an electrophilic
aromatic substitution under the reaction conditions. The alkyne 9 could easily be hydrogenated to give the
alkene 10 using palladium on carbon poisoned with quinoline under a H2-atmosphere in acetone at rt for
2.5 h in 79%.12 The diol rac-11 was synthesised using the Upjohn conditions13 with catalytic amounts of
potassium osmate(VI) dihydrate, DABCO and NMO in acetone at 0 °C for 3 d in 72%. Reaction of
rac-11 with methanesulfonyl chloride in pyridine at 0 °C and subsequent nucleophilic substitution most
probably via a primary formed methanesulfonate using potassium carbonate in methanol at rt for 3 h
furnished the desired epoxide rac-12 in 48% yield.14 Lithium halogen exchange with n-BuLi in THF at
78 °C up to rt for 20 h yielded rac-13 in 62% yield.15 Transformation into the desired seco-drug rac-3

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was performed using Appel conditions with triphenylphosphine and carbon tetrachloride in
1,2-dichloroethane at 50 °C for 18 h in 85% yield.16
At this stage we did not try to transform 3 into 4, since due to our experience with the seco-drugs of
ducarmycin SA (1) analogues it seemed to be more appropriate to use the seco-drug in the in vitro assays.
Thus, as already mentioned it could be expected that 3 is transformed in situ into 4 in the cell culture
medium.
OH
O
COOH
NH2
COOH
OH
a
b
N
H
OH
5
6
7
O
OH
Br
O
OH
d
c
N
H
O
N
H
OH
Br
9
8
O
OH
O
OH
f
e
N
O
N
H
O
OH
H
Br
Br
OH
10
rac-11
O
OH
OH
O
OH
i
h
g
3
rac-
N
N
H
O
O
H
O
Br
13
rac-
12
rac-
Scheme 1. Synthesis of racemic seco-Drug 3. a) NH4OH (aq.), ZnCl2, 190 °C, 4.5 d, 60%; b)
phloroglucinol, p-TsOH (cat.), n-heptanol, reflux, 19 h, 59%; c) NBS, ZnCl2, acetone, 78 °C, 2 h, 59%;
d) K2CO3, 3-chloro-3-methyl-1-butyne, CuCl (cat.), DMF, rt, 24 h, 68%; e) Pd/C (cat.), quinoline, H2
(1 atm), acetone, rt, 2.5 h, 79%; f) K2OsO4·2H2O (cat.), NMO, DABCO, acetone, 0 °C, 3 d, 72%; g)
MsCl, pyridine, 0 °C, 30 min then K2CO3, MeOH, rt, 3 h, 48%; h) n-BuLi, THF, 78 °C to rt, 20 h, 62%;
i) PPh3, CCl4, DCE, 50 °C, 18 h, 85%. p-TsOH = para-toluenesulfonic acid, NBS = N-bromosuccinimide,
DMF = dimethylformamide, NMO = N-methylmorpholine N-oxide, DABCO = 1,4-diazabicyclo[2.2.2]-
octane, MsCl = methanesulfonyl chloride, MeOH = methanol, n-BuLi = n-butyllithium, THF =
tetrahydrofuran, DCE = 1,2-dichloroethene.

HETEROCYCLES, Vol. 86, No. 1, 2012
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In-vitro-cytotoxicity tests: The in-vitro-cytotoxicity test of the new hybrid 3 was performed with
adherent growing cells of the human bronchial carcinoma cell line A549 determining the colony forming
ability; seco-drug rac-3 showed an IC50 value of 1040 nm. For comparison the same test was subjected to
acronycine 2 which was synthesized according to a known procedure17 starting from phloroglucinol and
anthranilic acid (2-aminobenzoic acid) in three steps showing an IC50 value of 1140 nm. For an evaluation
of the advantage of the new hybrid natural product 3 as a drug candidate its in vivo bioactivity including
its systemic toxicity will be studied. Moreover, compound 3 allows ample structural variations as the
introduction of a tertiary amino functionality to improve water solubility by formation of a salt.
CONCLUSION
We have designed and biologically evaluated the novel acronycine/seco-duocarmycin hybrid natural
product 3 by combining parts of acronycine (2) with a chloromethyl heterocyclic moiety condensed to a
phenol as found in seco-duocarmycin. This could form compound 4 in situ with the bioactive
spirocyclopropyldienenone moiety located in 1. The new hybrid shows a slightly higher cytotoxicity than
acronycine (2), although it does not contain a double bond which could be transformed in situ into an
epoxide as anticipated for the mode of action of 2. Thus, we have developed a new anticancer agent on
the basis of the hybrid concept, which might be of interest for further development.
EXPERIMENTAL
General: All reactions were performed under argon in flame-dried flasks. All solvents were dried and
distilled prior to use by usual laboratory methods. All reagents obtained from commercial sources were
used without further purification. Thin-layer chromatography (TLC) was performed on precoated silica
gel plates (TLC silica gel 60 F254, Merck) and silica gel 60 (0.032–0.063 mm, Merck) was used for
column chromatography. Phosphomolybdic acid in MeOH (PMA) or vanillin in methanolic sulphuric
acid were used as staining reagents for TLC. UV spectra were recorded in MCN or MeOH with a
Perkin–Elmer Lambda 2 or a JASCO V-630 spectrometer. IR spectra were recorded with a JASCO
1
13
FT/IR-4100 spectrometer. All substances were applied neat on an ATR unit. H and C NMR spectra
were recorded on a Varian Mercury-300, Unity-300, Inova-500 and Inova-600 spectrometer and a Bruker
AMX-300 spectrometer in CDCl3. Chemical shifts are given in ppm relative to tetramethylsilane (TMS),
coupling constants J in Hertz. The solvent signals were used as references and the chemical shifts
converted to the TMS scale (CHCl3: δH = 7.24 ppm, δC = 77.36 ppm). Multiplicities of 13C NMR peaks
were determined with the APT pulse sequence. Mass spectra were measured with a Finnigan MAT 95,
TSQ 7000 and LCQ instrument. HRMS was performed with a 7 T FTICR-MS APEX IV (Bruker). The

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following abbreviations are used in the text: EtOAc = ethyl acetate, PE = petroleum ether (bp 35–60 °C).
4-Bromo-3-(2,3-dihydroxy-1,1-dimethylpropoxy)-1-hydroxy-5H-benzo[b]acridin-12-one (rac-11):
To a solution of alkene 10 (224 mg, 529 mol, 1.00 equiv.) in acetone (10 mL) and H2O (2 mL) was
added NMO (92.9 mg, 793 mol, 1.50 equiv.), DABCO (89.0 mg, 793 mol, 1.50 equiv.) and
K2OsO4•2H2O (19.5 mg, 52.9 mol, 0.10 equiv.). The reaction mixture was stirred at 0 °C for 3 d, sat. aq.
NaHSO3-solution (2 mL) was added, the solution was further stirred for 10 min, then the volatile
compounds were evaporated under reduced pressure. The remaining suspension was diluted in 1 N HCl
(2 mL) and extracted with EtOAc (4 x 20 mL), the organic layer was dried over MgSO4 and silica gel
(1 g) was added. Removal of the solvents under reduced pressure and purification on silica gel
(PE/EtOAc = 1:1 to 100% EtOAc) gave rac-11 (174 mg, 380 mol, 72%) as a dark orange solid. Rf =
0.17 (PE/EtOAc = 1:1); 1H-NMR (301 MHz, DMSO): δ = 1.43, 1.47 (s, 6 H, 2 x 1'-CH3), 3.47 (ddd, J =
11.0, 8.0, 5.3 Hz, 1 H, 3'-Ha), 3.74 (ddd, J = 8.1, 5.2, 2.9 Hz, 1 H, 2'-H), 3.86 (ddd, J = 11.0, 6.0, 2.8 Hz,
1 H, 3'-Hb), 4.49 (t, J = 5.7 Hz, 1 H, 3'-OH), 5.11 (d, J = 5.2 Hz, 1 H, 2'O-H), 6.63 (s, 1 H, 2-H),
7.38–7.53 (m, 1 H, 8-H), 7.61 (dd, J = 11.1, 4.0 Hz, 1 H, 9-H), 7.93 (d, J = 8.4 Hz, 1 H, 7-H), 8.15 (d, J =
8.2 Hz, 1 H, 10-H), 8.50 (s, 1 H, 6-H), 8.88 (s, 1 H, 11-H), 10.54 (s, 1 H, NH), 14.26 (s, 1 H, 1-OH);
13C-NMR (75 MHz, DMSO): δ = 22.0, 24.2 (2 x 1'-CH3), 62.0 (C-3'), 76.9 (C-2'), 86.0 (C-1'), 90.4 (C-4),
99.5 (C-2), 103.5 (C-12a), 113.6 (C-6), 119.1 (C-5a), 124.6 (C-8), 126.2 (C-7), 126.6 (C-11), 128.0
(C-6a), 128.7 (C-9), 129.3 (C-10), 135.8 (C-10a), 136.9 (C-11a), 140.5 (C-4a), 159.4 (C-3), 162.5 (C-1),
181.5 (C-12); HRMS (ESI) m/z calcd. for C22H20BrNO5: 454.0296 [M-H+]-, found: 454.0292.
4-Bromo-1-hydroxy-3-(1-methyl-1-oxiranylethoxy)-5H-benzo[b]acridin-12-one (rac-12): A solution
of compound rac-11 (347 mg, 756 mol, 1.00 equiv.) in pyridine (13 mL) was stirred at 0 °C for 30 min,
then mesyl chloride (117 L, 1.51 mmol, 2.00 equiv.) was added and stirring was continued for 1 h. After
evaporation of the volatile compounds under reduced pressure the residue was dissolved in MeOH
(20 mL), then K2CO3 (523 mg, 3.78 mmol, 5.00 equiv.) was added and the dark red solution was stirred
for 3 h at rt. The solvent was evaporated at rt, ice-cold 1 N HCl (5 mL) was added and the aqueous layer
extracted with EtOAc (3 x 10 mL). After drying over Na2SO4 silica gel (2 g) was added and the volatile
compounds were removed under reduced pressure to give rac-12 (160 mg, 363 mol, 48%) as an orange
solid after purification on silica gel (PE/EtOAc = 4:1 to 3:1 to 2:1). Rf = 0.71 (PE/EtOAc = 2:1);
1H-NMR (301 MHz, DMSO): δ = 1.32, 1.50 (s, 6 H, 2 x 1'-CH3), 2.84 (dd, J = 4.7, 2.8 Hz, 1 H, 3'-Ha),
2.90 (t, J = 4.5 Hz, 1 H, 3'-Hb), 3.35 (dd, J = 4.3, 2.8 Hz, 1 H, 2'-H), 6.67 (s, 1 H, 2-H), 7.46 (d, J = 7.9
Hz, 1 H, 8-H), 7.59 (d, J = 7.2 Hz, 1 H, 9-H), 7.91 (d, J = 8.3 Hz, 1 H, 7-H), 8.13 (d, J = 8.3 Hz, 1 H,
13
10-H), 8.48 (s, 1 H, 6-H), 8.86 (s, 1 H, 11-H), 10.53 (s, 1 H, NH), 14.26 (s, 1 H, 1-OH); C-NMR (75
MHz, DMSO): δ = 20.1, 25.0 (2 x 1'-CH3), 44.6 (C-3'), 56.5 (C-2'), 82.4 (C-1'), 89.6 (C-4), 98.7 (C-2),

HETEROCYCLES, Vol. 86, No. 1, 2012
431
103.5 (C-12a), 113.6 (C-6), 119.1 (C-5a), 124.5 (C-8), 126.2 (C-7), 126.5 (C-11), 127.9 (C-6a), 128.7
(C-9), 129.3 (C-10), 135.8 (C-10a), 136.8 (C-11a), 140.4 (C-4a), 158.8 (C-3), 162.7 (C-1), 181.5 (C-12);
HRMS (ESI) m/z calcd. for C22H18BrNO4: 438.0346 [M-H+]-, found: 438.0330.
5-Hydroxy-1-(hydroxymethyl)-2,2-dimethyl-1,2-dihydrobenzo[b]furo[3,2-h]acridin-6(13H)-one
(rac-13): Epoxide rac-12 (59.4 mg, 135 mol, 1.00 equiv.) was dissolved in THF (10 mL), cooled to
78 °C and stirred for 15 min at that temperature. n-BuLi (205 L, 472 mol, 3.50 equiv., 2.5 M in
hexane) was added at 78 °C and the reaction was allowed to warm to rt within 20 h. Sat. aq. NH4Cl-sol.
(2 mL) was added, the aqueous layer extracted with EtOAc (3 x 20 mL), the organic layer dried over
MgSO4, silica gel (250 mg) was added and the volatile compounds were removed under reduced pressure.
rac-13 (30.3 mg, 83.9 mol, 62%) was obtained after purification on silica gel (PE/EtOAc = 3:1  2:1)
1
as an orange solid. Rf = 0.21 (PE/EtOAc = 2:1); H-NMR (301 MHz, DMSO): δ = 1.42, 1.50 (s, 6 H,
2 x 2-CH3), 3.45 (dd, J = 8.0, 4.4 Hz, 1 H, 1-H), 3.73 (t, J = 9.3 Hz, 1 H, 1'-Ha), 3.93 (dd, J = 10.5, 4.2 Hz,
1 H, 1'-Hb), 5.96 (s, 1 H, 1'-OH), 6.01 (s, 1 H, 4-H), 7.42 (ddd, J = 8.0, 6.7, 1.1 Hz, 1 H, 10-H), 7.58 (ddd,
J = 8.3, 6.7, 1.2 Hz, 1 H, 9-H), 7.85 (s, 1 H, 12-H), 7.95 (d, J = 8.1 Hz, 1 H, 11-H), 8.11 (d, J = 8.3 Hz,
1 H, 8-H), 8.86 (s, 1 H, 7-H), 11.49 (s, 1 H, NH), 14.53 (s, 1 H, 5-OH); 13C-NMR (75 MHz, DMSO): δ =
22.0, 28.4 (2 x 2-CH3), 51.0 (C-1), 60.1 (1-CH2), 89.9 (C-4), 90.1 (C-2), 102.4 (C-5a), 102.6 (C-13b),
111.4 (C-12), 119.5 (C-12a), 124.1 (C-10), 126.2 (C-7), 126.3 (C-11), 127.7 (C-11a), 128.4 (C-9), 129.3
(C-8), 135.7 (C-7a), 136.9 (C-6a), 139.8 (C-13a), 165.0 (C-3a), 165.3 (C-5), 180.9 (C-6); HRMS (ESI)
m/z calcd. for C22H19NO4: 360.1241 [M-H+]-, found: 360.1236.
1-(Chloromethyl)-5-hydroxy-2,2-dimethyl-1,2-dihydrobenzo[b]furo[3,2-h]acridin-6(13H)-one
(rac-3): Alcohol rac-13 (9.30 mg, 25.7 mol, 1.00 equiv), PPh3 (20.3 mg, 77.2 mol, 3.0 equiv.) and
CCl4 (23.0 L, 232 mmol, 9.00 equiv.) were dissolved in DCE (6 mL) and stirred for 18 h at 50 °C in a
pressure flask. Silica gel (50 mg) was added, removal of the solvent under reduced pressure and
purification on silica gel (PE/EtOAc = 10:1) gave rac-3 (8.31 mg, 21.9 mol, 85%) as an orange solid. Rf
= 0.71 (PE/EtOAc = 2:1); 1H-NMR (600 MHz, DMSO): δ = 1.42, 1.71 (s, 6 H, 2 x 2-CH3), 3.77 (dd, J =
6.9, 2.5 Hz, 1 H, 1-H), 3.95 (dd, J = 12.1, 2.5 Hz, 1 H, 1'-Ha), 4.01 (dd, J = 12.0, 7.0 Hz, 1 H, 1'-Hb), 6.05
(s, 1 H, 4-H), 7.46 (mc, 1 H, 10-H), 7.62 (mc, 1 H, 9-H), 8.00 (d, J = 8.7 Hz, 1 H, 11-H), 8.09 (s, 1 H,
12-H), 8.16 (d, J = 8.4 Hz, 1 H, 8-H), 8.90 (s, 1 H, 7-H), 11.12 (s, 1 H, NH), 14.63 (s, 1 H, 5-OH);
13C-NMR (126 MHz, DMSO): δ = 21.6, 28.7 (2 x 2-CH3), 43.0 (C-1'), 48.7 (C-1), 89.9 (C-4), 90.3 (C-2),
100.4 (C-13b), 102.4 (C-5a), 112.0 (C-12), 119.6 (C-12a), 124.3 (C-10), 126.2 (C-7), 126.4 (C-11), 127.7
(C-11a), 128.5 (C-9), 129.3 (C-8), 135.6 (C-7a), 137.1 (C-6a), 139.7 (C-13a), 165.2 (C-3a), 165.6 (C-5),
181.0 (C-6); HRMS (ESI) m/z calcd. for C22H19ClNO3: 378.0902 [M-H+]-, found: 378.0886.

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ACKNOWLEDGEMENTS
We would like to thank the Fonds of the Chemical Industry for generous financial support. J.R.R. and
S.C.D. thank the Konrad-Adenauer-Foundation for a Doctoral Fellowship.
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