SUPPORTING INFORMATION

Design, synthesis, in silico and in vitro evaluation of novel pyrimidine phosphonate molecule

revealed potential cytotoxicity against breast cancer cells

Nanda kumar Yellapu1#. Navya Atluri2#. Kalpana Kandlapalli3a. Raveendrababu Killaru. Jhansi Rani Vangavaragu4. Hariprasad Osuru5.

Sarma PVGK3b. Bhaskar Matcha1*

1Division of Animal Biotechnology, Department of Zoology, Sri Venkateswara University, Tirupati – 517 502, India

2Department of Applied Microbiology, Sri Padmavati Mahila Visvavidyalayam, Tirupati – 517502, Andhra Pradesh, India

3aDepartment of Biochemistry & 3bDepartment of Biotechnology, Sri Venkateswara Institute of Medical Sceicnes, Tirupati – 517507, Tirupati,

India

4Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 66047 – USA

5Department of Pathology, University Of Virginia, Charlottesville, Virginia – USA

List of Contents----------------------------------------------------------------------------------------------------------------------------------page No.

1. ADME properties predicted for compounds 6a-6i…………………………………………………………………...……………….S2

2. Molecular docking interaction of 6a-6i with aromatase active site…………………………………………………………….....S3-S4

3. 1H NMR, 13C NMR, 31P NMR spectra’s and HRMS spectra for compound 6i………………………………………………….S5-S8

S1

Compound

Human intestinal

absorption (%)

in vitro Caco-2 cell permeability

(nm/sec)

in vitro MDCK cell

permeability (nm/sec)

in vitro skin permeability

(logKp, cm/hour)

in vitro plasma protein

binding (%)

in vivo blood-brain barrier penetration

([brain]/[blood])6a 65.21 1.18 0.34 -3.14 85.61 0.516b 60.38 0.39 1.02 -3.59 72.87 0.446c 80.82 0.57 1.50 -4.06 51.69 0.366d 78.32 0.54 2.11 -4.25 23.57 0.406e 56.36 0.39 1.46 -3.84 48.24 0.426f 56.36 0.39 0.92 -3.84 43.89 0.426g 90.71 2.97 0.51 -3.95 44.80 0.506h 91.93 3.14 0.41 -3.67 66.44 0.526i 85.04 14.82 0.39 -3.46 69.57 0.27

Table S1: ADME properties predicted for the compounds 6a-6i.

S2

6a 6b 6c

6d 6e 6f

S3

6g 6h 6i

Exemestane

Table S2: Molecular docking interaction of compounds 6a-6i in the Aromatase active site.

S4

PO

O

O

O

NH

N

O

O

O

OH

0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5f1 (ppm)

2.96

5.99

2.85

0.29

3.99

8.02

0.99

0.94

2.01

1.94

0.98

1.00

1.09

1.10

1.10

1.12

1.21

1.21

1.22

1.22

1.23

1.24

1.25

1.99

2.24

2.50

DM

SO2.

50 D

MSO

2.50

DM

SO2.

51 D

MSO

2.51

DM

SO2.

732.

732.

89

3.35

3.88

3.90

3.97

3.99

4.03

4.03

4.04

4.04

4.06

4.07

5.09

5.10

5.76

5.76

6.87

6.88

6.89

6.89

6.90

7.13

7.13

7.14

7.15

7.15

7.68

7.68

7.69

7.69

9.16

9.17

S5

N

NH

O

O

O

HO

O

PO

OO

C-8C-4

C-5

C-1 C-2C-3

C-6

C-7

C-9

C-10

C-11

C-12

C-13

C-14

C-15

C-16

C-17

C-18

C-19C-20

C-21

102030405060708090100110120130140150160170f1 (ppm)

14.0

516

.21

16.2

617

.71

53.2

754

.87

59.1

061

.66

61.7

163

.45

64.7

466

.67

66.8

370

.79

70.8

8

99.4

799

.49

114.

16

127.

37

137.

15

148.

00

152.

10

157.

51

165.

31

S6

-240-220-200-180-160-140-120-100-80-60-40-20020406080100120140f1 (ppm)

1.00

21.8

921

.91

S7

S8